Advertisement
Research ArticleMinireview—A Latin American Perspective On G Protein-Coupled Receptors

Corticotropin-Releasing Factor Receptors and Their Interacting Proteins: Functional Consequences

Paula G. Slater, Hector E. Yarur and Katia Gysling
Molecular Pharmacology November 2016, 90 (5) 627-632; DOI: https://doi.org/10.1124/mol.116.104927

Abstract

The corticotropin-releasing factor (CRF) system, which is involved in stress, addiction, and anxiety disorders such as depression, acts through G-protein–coupled receptors (GPCRs) known as type-1 and type-2 CRF receptors. The purpose of this review is to highlight recent advances in the interactions of CRF receptors with other GPCRs and non-GPCR proteins and their associated functional consequences. A better understanding of these interactions may generate new pharmacological alternatives for the treatment of addiction and stress-related disorders.

Introduction

Compelling evidence exists that indicates that G-protein–coupled receptors (GPCRs) exist as dimers/oligomers that are formed by identical receptor molecules (homomers) or by different receptor molecules (heteromers) as opposed to monomers (Franco et al., 2008). The criteria to consider a protein-protein interaction between receptors as a heteromer has been described by Pin et al. (2007), and the available evidence shows that the assembly between GPCRs is fundamental for many functional aspects of GPCRs; the multimers usually exhibit different properties than the protomers (Terrillon and Bouvier, 2004; Szafran et al., 2013). The following situations have been associated with the homo- and heteromerization of GPCRs: 1) the interaction between GPCRs is fundamental for the correct functioning of some receptors; 2) the homo- or heteromerization can be constitutive or regulated by a ligand; 3) GPCR assembly can change the pharmacological properties of the individual receptors, as demonstrated by the affinity for a ligand increasing or diminishing and the occurrence of a positive or negative cooperativity between different ligands; 4) a change in signal transduction, either potentiation, attenuation, or changes in the G-protein subfamily coupled to the receptors, can occur in both homomers and heteromers; and 5) endocytosis of some GPCRs can also be affected; the stimulation of one protomer can be sufficient for the internalization of both receptors (Terrillon and Bouvier, 2004).

In addition to homo- and heteromerization, increasing evidence shows that GPCRs may also interact with the non-GPCR proteins that regulate their trafficking to the plasma membrane and/or their function (McLatchie et al., 1998; Doly and Marullo, 2015). Evidence showing that GPCRs homo- and heteromerize, and that GPCR interactions with other non-GPCR proteins confers new and different receptor properties, has opened new avenues for the development of more selective pharmacological tools (Rozenfeld and Devi, 2010).

In this review, we summarize the existing data regarding homo- and heteromerization of corticotropin-releasing factor (CRF) receptors and their interaction with non-GPCR proteins.

Description of the Corticotropin-Releasing Factor System

The CRF system is composed of four neuropeptides: CRF and urocortin 1–3, type-1 (CRF1R) and type-2 (CRF2R) CRF receptors, and CRF binding proteins (CRF-BPs) (Bale and Vale, 2004; Gysling, 2012). CRF and urocortin 1 have high affinity for both types of CRF receptors, whereas urocortin 2 and urocortin 3 have high affinity only for CRF2R, and CRF and urocortin 1 have high affinity for CRF-BP. Urocortin 2 has low affinity and urocortin 3 has no affinity for CRF-BP (Bale and Vale, 2004).

The human CRF receptors (CRFRs) are encoded by different genes, but the proteins share high sequence homology (70%). The lowest degree of homology is found in the N-terminal domain (40%) (Dautzenberg and Hauger, 2002), and many splice variants exist for both receptors. The CRF1R cDNA sequence predicts a protein of 415–420 amino acids with one functional and several nonfunctional isoforms (Dautzenberg et al., 2001; Grammatopoulos and Chrousos, 2002), whereas CRF2R has three known functional isoforms. The type-2 α CRF receptor (CRF2αR) is 411 amino acids in length (Liaw et al., 1996), and the first 34 amino acids are replaced by a sequence of 61 amino acids in the case of type-2 β CRF receptor (CRF2βR), which encodes a protein of 438 amino acids (Valdenaire et al., 1997; Grammatopoulos and Chrousos, 2002). The same 34 amino acids are changed by a sequence of 20 amino acids in the case of the type-2 γ CRF receptor (CRF2γR) protein, which is 397 amino acids long (Kostich et al., 1998). Besides the N-terminal domain differences, the three CRF2R splice variants have different tissue distributions; CRF2αR is the most abundant isoform in the brain (Dautzenberg and Hauger, 2002; Hauger et al., 2006), and CRF2βR is found almost exclusively in peripheral organs and systems, such as the cardiovascular system, intestine, uterus, liver, and placenta (Dautzenberg and Hauger, 2002).

Homo- and Heteromerization of CRF Receptors

Homodimerization of CRF Receptors.

CRF1R (Kraetke et al., 2005) and CRF2βR (Milan-Lobo et al., 2009), but not CRF2αR (Teichmann et al., 2012), are capable of homodimerization. CRF1R was the first class B GPCR to be described as having the ability to form homomers. Using the methodology of fluorescence resonance energy transfer (FRET) in HEK293T cells, Kraetke et al. (2005) showed that CRF1R form homomers in the plasma membrane and in intracellular compartments. Interestingly, the level of CRF1R homodimerization was unaffected by the presence of different CRF1R agonists, indicating that the homomer assembly does not require a ligand. The presence of homomers in intracellular compartments indicates that their assembly may start intracellularly. As with the GABAB receptor (White et al., 1998), CRF1R homodimerization in intracellular compartments could regulate the presence of CRF1R in the plasma membrane. It has also been shown that CRF2βR homodimerizes in HEK293 transfected cells. Milan-Lobo et al. (2009) compared the homodimerization of CRF1R and CRF2βR and observed that both receptors form homomers in the absence of ligand. Further studies should address the functional consequences of their homodimerization.

CRF1R and CRF2βR differ from CRF2αR in the structure of the N-terminal extracellular domain. The N-terminal extracellular domain of the three receptors form the same fold, but the CRF2αR N terminus contains a hydrophobic α-helix formed by its noncleavable pseudosignal peptide, in contrast to CRF1R and CRF2βR, which have a cleavable signal peptide (Rutz et al., 2006; Pal et al., 2010). The capacity of CRF1R and CRF2αR to form homomers or monomers is due to the absence or presence of the signal peptide, respectively (Fig. 1). Utilizing chimeras and FRET analyses, Teichmann et al. (2012) elegantly showed that the pseudosignal peptide of CRF2αR is responsible for the monomeric form of the receptor; the CRF1R chimera containing the CRF2αR noncleavable pseudosignal peptide prevented receptor homodimerization, and the CRF2αR chimera containing the CRF1R cleavable signal peptide was able to homodimerize.

Fig. 1.
Fig. 1.

Schematic representation of CRF1R and CRF2αR highlighting protein interactions of both receptors. The presence of the noncleavable signal peptide in the N terminus of CRF2αR determines significant differences in the repertoire of interacting proteins with each receptor. The differences in the amino acid sequence in the C terminus of both receptors determine the interaction of CRF1R, but not CRF2αR, with MAGUK proteins and with 5-HT2R. TAA, tryptophan, alanine, alanine.

Teichmann et al. (2014) showed that CRF1R transfected into HEK293T cells exists in the plasma membrane as monomers and homodimers, and that the formation of higher-level oligomers was not observed. In addition, the experiments showed that 22–29% of CRF1R present in the plasma membrane was homodimerized, and that this percentage was not modified by the presence of sauvagine, a CRFR agonist.

The ability of CRF1R to exist as either a monomer or homodimer could affect its downstream signaling. Schulz et al. (2010) showed that the activation of CRF1R yields a biphasic concentration-response curve for cAMP accumulation in the cell, which is generated by the association of the receptor to a Gs-protein at low agonist concentration and to a Gi-protein at high agonist concentration. On the other hand, CRF2αR yields a monophasic concentration-response curve for cAMP cell accumulation, which is generated by the association of the receptor to only the Gs-protein. These signaling characteristics were transferable when the signal peptide was exchanged, and the biogenesis and the cell surface levels of the CRFRs were also affected (Rutz et al., 2006; Schulz et al., 2010). The pseudosignal peptide, responsible for the monomeric form of CRF2αR, leads to an immature nonglycosylated state of the receptor and low levels of CRF2αR in the cell surface. In contrast, the cleavage of the signal peptide in CRF1R leads to high levels of the receptor in the cell surface (Fig. 1).

Heteromerization of CRF1R.

There is evidence of heteromerization of CRF1R with the vasopressin (AVP) V1b receptor (V1bR) (Murat et al., 2012), the orexin 1 receptor (OX1R) (Navarro et al., 2015), and the 5-hydroxytriptamine (5-HT) receptor (5-HT2R) (Magalhaes et al., 2010). AVP and CRF release adrenocorticotropic hormone (ACTH) from the anterior pituitary, and the receptors involved are V1bR and CRF1R, respectively (Guillon et al., 1987; Liebsch et al., 1999). Gillies et al. (1982) showed that CRF and AVP have a synergistic effect on the release of ACTH from the pituitary, and Young et al. (2007), using coimmunoprecipitation (Co-IP) and bioluminescence resonance energy transfer (BRET) techniques, showed that V1bR and CRF1R are able to interact in Chinese hamster ovary cells. The interaction of V1bR and CRF1R is not dependent on the presence of their agonists, suggesting that their heteromerization is constitutive and not a process regulated by their ligands. The presence of agonists for V1bR and CRF1R does not modify the number of receptors that bind to their ligands in the plasma membrane. Murat et al. (2012) addressed the question of how the synergistic action of AVP and CRF takes place in the pituitary. These authors documented the heteromerization of V1bR with CRF1R using BRET, Co-IP, and receptor rescue experiments, and showed that the activation of either V1bR or CRF1R, naturally expressed in bovine chromaffin cells, was able to induce catecholamine secretion. Interestingly, the coinfusion of both agonists induced a synergistic action on catecholamine secretion. Considering the evidence presented earlier, it is clear that the presence of the V1bR/CRF1R heteromer is crucial for the synergistic effect of AVP and CRF for releasing ACTH. The functional relevance of this heteromer may explain the observations made in knockout mice for V1bR (Tanoue et al., 2004); in these mice, the circulating levels of ACTH were lower at resting conditions and under stress induced by forced swimming (Tanoue et al., 2004).

CRF plays a key role in the plastic changes associated with stress and drug abuse (Shaham et al., 1998; Ungless et al., 2003; Williams et al., 2014; Zorrilla et al., 2014; Sotomayor-Zárate et al., 2015). CRF1R is involved in the sensitization of dopaminergic neurons by CRF in the ventral tegmental area (VTA) after cocaine administration and in stress-induced relapse to cocaine seeking (Hahn et al., 2009; Blacktop et al., 2011). The neuropeptide orexin-A (OX-A) has also been involved in relapse to cocaine seeking (Boutrel et al., 2005). Relapse was prevented by a nonselective antagonist of CRF receptors and a selective antagonist of the OX1R. Wang et al. (2009) reported that VTA CRF and OX-A were involved in stress-induced relapse to cocaine seeking by independent mechanisms.

Navarro et al. (2015) investigated whether CRF1R and OX1R were able to form heteromers in cell lines and in vivo, and obtained compelling evidence of the heteromerization of CRF1R and OX1R that determines a negative cross-talk between both receptors. The use of peptides bearing the sequence of transmembrane domains, TM1 and TM5 of OX1R, allowed the disassembly of the heteromer and consequently the negative cross-signaling between both receptors, confirming that the integrity of the heteromer is crucial for the cross-talk between the receptors. Interestingly, the negative cross-talk between CRF1R and OX1R was also observed in VTA slices. CRF1R signals through Gs-protein, increasing cAMP production, whereas OX1R signals though Gi-protein, decreasing cAMP synthesis. The infusion of an antagonist for one of the receptors antagonized the cAMP effect of the agonist for the other receptor. The negative cross-talk between CRF and OX-A was perceived not only at the level of second messengers, but also at the level of dopamine release. The release of dopamine in the VTA was antagonized by infusing antagonists for CRF1R and OX1R, but was recovered by infusing the agonists for the receptors in the VTA. Therefore, the CRF1R/OX1R heteromer is present in the VTA and plays a role in controlling dopamine release. Further studies should address the apparent discrepancies between this work and the independent control exerted by CRF and OX-A previously described (Wang et al., 2009). Navarro et al. (2015) also found that the σ1 receptor (σ1R) was able to oligomerize with the CRF1R/OX1R heteromer, specifically with CRF1R. The activation of σ1R eliminates the negative cross-talk between CRF and OX-A in the VTA (Navarro et al., 2015). It is tempting to suggest that the activation of σ1R may explain the apparent differences between the work of Wang et al. (2009) and that of Navarro et al. (2015). It was stated that cocaine is an agonist for σ1R (Kourrich et al., 2012), and this evidence suggests that the CRF1R/σ1R/OX1R oligomer may be a potential target for the pharmacological treatment of addiction.

The CRF system also plays a key role in anxiety disorders, such as depression (Reul and Holsboer, 2002; Kehne, 2007). CRF and 5-HT are known to influence and modulate depressive and anxiety-like behaviors (Müller et al., 2003; Bockaert et al., 2006), and Tan et al. (2004) demonstrated that the activation of CRF1R in neurons of the prefrontal cortex (PFC) results in the modulation of 5-HT2R signaling. The sIPSC in the PFC were increased by stimulation with 5-HT in PFC slices pretreated with CRF or obtained from stressed animals, suggesting that CRF1R and 5-HT2R may interact in the PFC. Magalhaes et al. (2010) showed that the activation of CRF1R increased inositol phosphate formation induced by the activation of 5-HT2R in heterologous cell cultures as well as in mouse cortical neurons. The increase in inositol phosphate produced by pretreatment with CRF is not due to CRF1R activation; the stimulation of CRF1R alone does not lead to the formation of inositol phosphate. Interestingly, when the cells were first pretreated with 5-HT and thereafter with a CRF1R agonist, no significant increase in cAMP production in response to the activation of CRF1R was observed. Thus, the synergistic effect between both receptors is observed only when CRF1R is stimulated before 5-HT2R. The functional consequence of the CRF1R/5-HT2R interaction is that previous exposure of the prefrontal cortex to CRF increases 5-HT2–dependent behavior induced by 2,5-dimethoxy-4-iodoamphetamine (Magalhaes et al., 2010). Magalhaes et al. (2010) found that a subpopulation of neurons in the PFC express the CRF1 and 5-HT2A receptors. In the presence of CRF, both receptors underwent endocytosis and were located in intracellular vesicles. Subsequently, it was observed that the endocytosis and recycling of CRF1R were essential for the synergism between CRF1R and 5-HT2R. These authors also indicated that the interaction between 5-HT2R and CRF1R occurs through their PSD95/discs large/occludens zone 1 domains (PDZ)–binding domains in the carboxyl-terminal domain of both receptors. This is one of the critical differences between CRF1R and CRF2R, because the class I PDZ binding domain (STAV) is only found in CRF1R (Fig. 1). Therefore, CRF1R, but not CRF2αR or CRF2βR, is able to interact with 5-HT2R. Interestingly, it was proposed that this interaction is not direct and depends on a PDZ domain containing protein (Magalhaes et al., 2012). PDZ domains are usually the sites of interaction of non-GPCR proteins with GPCRs.

Heteromerization of CRF2R.

At present, there is only evidence of the heteromerization of CRF2αR with the dopamine type-1 receptor (D1R) (Fuenzalida et al., 2014), and this heteromer assembles in the absence of ligands. The evidence was obtained in HEK293T cells cotransfected with the receptors using FRET, BRET, Co-IP, and homogeneous time-resolved fluorescence to measure cAMP accumulation in the cells. It was also observed that the CRF2αR/D1R heteromer had a number of characteristics that were different from the protomers. First, the subcellular localization of the receptors changed. The D1R is located mainly in the cell surface (O’Dowd et al., 2005) and CRF2αR intracellularly (Waselus et al., 2009; Wood et al., 2013). However, when the receptors are coexpressed, the D1R is found mostly in the endoplasmic reticulum (ER) colocalizing with CRF2αR. Second, the signaling properties also changed. CRF2αR and D1R couple to Gs-protein, resulting in intracellular cAMP accumulation (Dautzenberg and Hauger, 2002; Neve et al., 2004), and the CRF2αR/D1R heteromer maintained the signaling through cAMP upon stimulation with CRF2αR and D1R agonists. However, the protein was also able to mobilize intracellular calcium upon stimulation with D1R agonist. Moreover, synergism was described between CRF2αR and D1R in the synaptic transmission from rat basolateral amygdala to the PFC (Orozco-Cabal et al., 2008). Utilizing electrophysiological approaches, the authors showed that the activation of either of these receptors increases cocaine-induced synaptic depression. When both receptors were activated, a positive cooperativity between both ligands was observed on synaptic depression. Moreover, after chronic cocaine use, the activation of both receptors induced synaptic facilitation; these results led the authors of the study to propose the existence of heteromers between dopamine and CRF receptors (Orozco-Cabal et al., 2008).

CRF Receptors and Their Interaction with Non-GPCR Proteins

Compelling evidence exists showing that GPCRs interact with specific non-GPCR proteins, and these interactions are very important in the regulation of the trafficking, maturation, cell surface expression, signaling, and/or desensitization of the receptors. These interacting proteins are called accessory or escort proteins (Achour et al., 2008; Roux and Cottrell, 2014).

Formerly, it was believed that GPCRs were found mainly in the plasma membrane ready to be activated by their ligands. It is now known that most GPCRs accumulate as stock of functional receptors, or ready to finish maturation, in the ER or Golgi apparatus, and they traffic to the plasma membrane when needed (Achour et al., 2008; Doly and Marullo, 2015). Two types of proteins, the gatekeepers and the escort proteins, jointly regulate the push and pull from the ER or Golgi apparatus to the plasma membrane. The gatekeepers are ER or Golgi apparatus resident proteins that interact and retain GPCRs in the respective cellular compartment. The release of the GPCRs from the ER or Golgi apparatus occurs only after a competitive displacement of the GPCR/gatekeeper interaction by a GPCR/escort protein interaction (Doly and Marullo, 2015).

Recently, the existence of CRFR escort proteins has been described. The receptor activity-modifying protein 2 (RAMP2), one of the most studied escort proteins, functions as a CRF1R escort protein, modifying cell surface expression and signaling of the receptor (Wootten et al., 2013). Using heterologous expression in cell cultures and enzyme-linked immunosorbent assays to measure plasma membrane protein expression, Wootten et al. (2013) determined that RAMP2 increases the plasma membrane expression of CRF1R. In addition, measuring cAMP production, calcium mobilization, and CRF1R/guanosine 5′-3-O-(thio)triphosphate binding, the authors showed that RAMP2 did not affect the ability of CRF1R to bind Gs-protein or of CRF1R agonists to stimulate cAMP production. Instead, it generated an increase in the ability of CRF1R to bind Gi/o/t/z-, Gq/11-, and G12/13–proteins, and CRF1R was now able to mobilize intracellular calcium.

Recently, it was shown that CRF-BP functions as a CRF2αR escort protein (Slater et al., 2016b). Using yeast two-hybrid assay and Co-IP in HEK293T cells extracts transfected with the corresponding proteins, it was shown that CRF-BP physically interacts with CRF2αR in an isoform-specific manner, and using confocal microscopy, it was determined that CRF-BP increases CRF2αR plasma membrane levels (Slater et al., 2016b). Moreover, endogenous CRF-BP and CRF2αR colocalize in cultured mesencephalic neurons (Slater et al., 2016b) and coexist in VTA synaptosomes (Slater et al., 2016a). Thus, this anatomic evidence indicates that CRF-BP and CRF2αR coexist in pre- and postsynaptic elements in the VTA.

CRF2αR is expressed mainly in the ER (Fuenzalida et al., 2014; Slater et al., 2016b), where it is retained due to its described interaction with the ER resident protein calnexin (Schulz et al., 2010). Calnexin interacts with the CRF2αR pseudosignal peptide (Schulz et al., 2010), and CRF-BP interacts with the N-terminal domain of CRF2αR (Slater et al., 2016b). Thus, it is tempting to suggest that a competitive displacement of the CRF2αR/calnexin interaction by CRF-BP is necessary for the receptor to reach the plasma membrane.

Furthermore, there is evidence of a glutamate neurotransmission potentiation role of CRF-BP over CRF signaling through CRF2R, both presynaptically (Wang et al., 2005, 2007) and postsynaptically (Ungless et al., 2003), in the VTA after cocaine experience or stress. Further studies are necessary to determine whether the interaction between CRF2αR and CRF-BP is related to the requirement of the CRF interaction with CRF-BP to potentiate this addictive and stress-related neuronal plasticity.

In addition, a family of synaptic proteins known as membrane-associated guanylate kinases (MAGUKs) is important for the assembly and signaling of other proteins. MAGUK proteins contain PDZ domains, which can interact with a variety of proteins. The interaction of MAGUK proteins with multiple receptors occurs through binding to the PDZ motifs present in the carboxyl-terminal domain of the receptors (Kim and Sheng, 2004; Dunn and Ferguson, 2015).

CRF1R interacts with several MAGUK proteins: PSD95, PSD93, SAP102, SAP97, and MAGI2 (Dunn et al., 2013, 2016; Walther et al., 2015). Dunn et al. (2013) showed the interaction between CRF1R and SAP97, an interaction dependent on the CRF1R PDZ domain that is not modified in the presence of agonists, such as CRF. Furthermore, SAP97 attenuates CRF-induced endocytosis of CRF1R, maintaining a higher level of CRF1R in the plasma membrane. On the other hand, the MAGUK protein PDZK1 interacts with CRF1R, increasing extracellular signal-related kinase 1/2 signaling (Walther et al., 2015). PSD95 also interacts with CRF1R, and similar to SAP97, PSD95 attenuates ligand-induced endocytosis of CRF1R. However, PSD95 does not detectably alter CRF1R signaling (Dunn et al., 2016). CRF1R has an STAV in its C-terminal domain (Magalhaes et al., 2010). Bender et al. (2015), using yeast two-hybrid assays and Co-IP in HEK293 cells and neuronal cultures, as well as the modification of the STAV sequence of CRF1R, documented that it is the C-terminal domain of CRF1R that interacts with the PDZ domains of MAGUK proteins. Therefore, although CRF1R has a PDZ-binding domain that can interact with various MAGUK proteins, not all MAGUK proteins regulate CRF1R in the same way.

After their agonists activate GPCRs, a process of desensitization occurs, which consists of preventing the GPCR/G-protein interaction followed by the endocytosis of the receptors. Usually, the desensitization process occurs due to the GPCR interacting protein, β-arrestin. The phosphorylation of the receptor by the GPCR kinases is necessary for its interaction with β-arrestins and for targeting clathrin-coated pits for endocytosis (Kohout and Lefkowitz, 2003). Both CRF2R and CRF1R have a high degree of sequence conservation of consensus sites for phosphorylation by several protein kinases, which could modulate CRFR function (Hauger et al., 2006). CRF1R is capable of recruiting β-arrestin 1 (Rasmussen et al., 2004) and β-arrestin 2 (Perry et al., 2005). Using confocal microcopy, Rasmussen et al. (2004) demonstrated that treatment with kinase inhibitors affects the recruitment of β-arrestin 1, but not CRF1R internalization. Thus, β-arrestin 1/CRF1R interaction is not necessary for CRF1R endocytosis in HEK293 cells. Similarly, β-arrestin 1 proteins do not internalize with CRF1R in primary cortical neurons (Holmes et al., 2006). Perry et al. (2005) showed that CRF1R is able to recruit β-arrestin 2 in HEK293 cells and in primary cortical neurons. Moreover, β-arrestin 2 internalizes with CRF1R in HEK293 cells, but not in cortical neurons. Using confocal microscopy, Hauger et al. (2013) demonstrated that CRF2αR can also recruit β-arrestin 2 in HEK293 cells in an agonist concentration–dependent manner, but they reported that β-arrestin 2 is not internalized with CRF2αR. Furthermore, Milan-Lobo et al. (2009) showed that both CRF2βR and CRF1R homomers recruited β-arrestin upon agonist stimulation. However, they observed that CRF1R, and not CRF2βR, was internalized. The available data for CRFR interacting proteins have been obtained with heterologous overexpression of the interacting partners. Protein overexpression could lead to nonphysiologic protein/protein interactions. Due to the potential relevance of these interactions, they should be studied in physiologic/physiopathologic states.

Conclusions

Increasing evidence shows that CRF receptors interact with themselves to form homomeric dimers (CRF1R and CRF2βR) and with other GPCRs to form heteromers (CRF1R and CRF2αR) (Fig. 1). At present, there is no evidence showing the interaction of CRF2βR with other GPCRs. In addition, CRF receptors interact with non-GPCR proteins that regulate their localization in the plasma membrane. CRF1R interacts with membrane-associated guanylate kinases, as well as with receptor activity–modifying protein 2 to increase its presence in the plasma membrane. CRF2αR, but not CRF2βR, interacts with CRF-BP, which facilitates its access to the plasma membrane. The interaction of these proteins has been observed only in heterologous overexpression assays. However, the anatomic evidence of their coexistence in specific neuronal phenotypes demands further in vivo studies to elucidate the potential contribution of the reviewed protein interactions in the stress response in health and disease. For instance, the reported interaction of CRF2αR with D1R and with CRF-BP may occur in the ventral tegmental area as well as in other brain regions involved in the interaction between stress and addiction. As proposed by Arzt and Holsboer (2006), selective signaling of CRF-R1 in different brain regions could be exploited to generate new pharmacological strategies to treat stress-related disorders. It is tempting to suggest that the differential signaling of CRF-R1 in different brain regions could be due to their interactions with other GPCRs or non-GPCR proteins. Thus, a better knowledge of such interactions and their functional consequences may open new pharmacological strategies to treat addictive behavior and stress-related disorders.

Authorship Contributions

Wrote or contributed to the writing of the manuscript: Slater, Yarur, Gysling.

Footnotes

    • Received April 26, 2016.
    • Accepted September 8, 2016.

  • ↵1 P.G.S. and H.E.Y. contributed equally to this work.

  • This work was supported by FONDECYT (Grant 1150244) and by CONICYT Ph.D. fellowships to P.G.S. and H.E.Y.

  • dx.doi.org/10.1124/mol.116.104927.

Abbreviations

ACTH
adrenocorticotropic hormone
AVP
vasopressin
BRET
bioluminescence resonance energy transfer
Co-IP
coimmunoprecipitation
CRF
corticotropin-releasing factor
CRF-BP
CRF binding protein
CRFR
CRF receptor
CRF1R
type-1 CRF receptor
CRF2R
type-2 CRF receptor
CRF2αR
type-2 α CRF receptor
CRF2βR
type-2 β CRF receptor
D1R
dopamine type-1 receptor
ER
endoplasmic reticulum
5-HT
5-hydroxytriptamine
5-HT2R
5-HT2 receptor
FRET
fluorescence resonance energy transfer
GPCR
G-protein–coupled receptor
MAGUK
membrane-associated guanylate kinase
OX-A
orexin-A
OX1R
orexin 1 receptor
PDZ
PSD95/discs large/occludens zone 1
PFC
prefrontal cortex
σ1R
σ1 receptor
RAMP2
receptor activity-modifying protein 2
STAV
class I PDZ binding domain
V1bR
AVP 1b receptor
VTA
ventral tegmental area

References

  1. ↵
    1. Achour L,
    2. Labbé-Jullié C,
    3. Scott MG, and
    4. Marullo S
    (2008) An escort for GPCRs: implications for regulation of receptor density at the cell surface. Trends Pharmacol Sci 29:528–535.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Arzt E and
    2. Holsboer F
    (2006) CRF signaling: molecular specificity for drug targeting in the CNS. Trends Pharmacol Sci 27:531–538.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Bale TL and
    2. Vale WW
    (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44:525–557.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Bender J,
    2. Engeholm M,
    3. Ederer MS,
    4. Breu J,
    5. Møller TC,
    6. Michalakis S,
    7. Rasko T,
    8. Wanker EE,
    9. Biel M,
    10. Martinez KL,
    11. et al.
    (2015) Corticotropin-releasing hormone receptor type 1 (CRHR1) clustering with MAGUKs Is mediated via Its C-terminal PDZ binding motif. PLoS One 10:e0136768.
    OpenUrlCrossRef
  5. ↵
    1. Blacktop JM,
    2. Seubert C,
    3. Baker DA,
    4. Ferda N,
    5. Lee G,
    6. Graf EN, and
    7. Mantsch JR
    (2011) Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2. J Neurosci 31:11396–11403.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Bockaert J,
    2. Claeysen S,
    3. Bécamel C,
    4. Dumuis A, and
    5. Marin P
    (2006) Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res 326:553–572.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Boutrel B,
    2. Kenny PJ,
    3. Specio SE,
    4. Martin-Fardon R,
    5. Markou A,
    6. Koob GF, and
    7. de Lecea L
    (2005) Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci USA 102:19168–19173.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Dautzenberg FM and
    2. Hauger RL
    (2002) The CRF peptide family and their receptors: yet more partners discovered. Trends Pharmacol Sci 23:71–77.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Dautzenberg FM,
    2. Kilpatrick GJ,
    3. Hauger RL, and
    4. Moreau J
    (2001) Molecular biology of the CRH receptors-- in the mood. Peptides 22:753–760.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Doly S and
    2. Marullo S
    (2015) Gatekeepers Controlling GPCR Export and Function. Trends Pharmacol Sci 36:636–644.
    OpenUrlCrossRef
  11. ↵
    1. Dunn HA,
    2. Chahal HS,
    3. Caetano FA,
    4. Holmes KD,
    5. Yuan GY,
    6. Parikh R,
    7. Heit B, and
    8. Ferguson SS
    (2016) PSD-95 regulates CRFR1 localization, trafficking and β-arrestin2 recruitment. Cell Signal 28:531–540.
    OpenUrlCrossRef
  12. ↵
    1. Dunn HA and
    2. Ferguson SS
    (2015) PDZ Protein Regulation of G Protein-Coupled Receptor Trafficking and Signaling Pathways. Mol Pharmacol 88:624–639.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Dunn HA,
    2. Walther C,
    3. Godin CM,
    4. Hall RA, and
    5. Ferguson SS
    (2013) Role of SAP97 protein in the regulation of corticotropin-releasing factor receptor 1 endocytosis and extracellular signal-regulated kinase 1/2 signaling. J Biol Chem 288:15023–15034.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Franco R,
    2. Casadó V,
    3. Cortés A,
    4. Mallol J,
    5. Ciruela F,
    6. Ferré S,
    7. Lluis C, and
    8. Canela EI
    (2008) G-protein-coupled receptor heteromers: function and ligand pharmacology. Br J Pharmacol 153 (Suppl 1):S90–S98.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Fuenzalida J,
    2. Galaz P,
    3. Araya KA,
    4. Slater PG,
    5. Blanco EH,
    6. Campusano JM,
    7. Ciruela F, and
    8. Gysling K
    (2014) Dopamine D1 and corticotrophin-releasing hormone type-2α receptors assemble into functionally interacting complexes in living cells. Br J Pharmacol 171:5650–5664.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Gillies GE,
    2. Linton EA, and
    3. Lowry PJ
    (1982) Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature 299:355–357.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Grammatopoulos DK and
    2. Chrousos GP
    (2002) Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists. Trends Endocrinol Metab 13:436–444.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Guillon G,
    2. Gaillard RC,
    3. Kehrer P,
    4. Schoenenberg P,
    5. Muller AF, and
    6. Jard S
    (1987) Vasopressin and angiotensin induce inositol lipid breakdown in rat adenohypophysial cells in primary culture. Regul Pept 18:119–129.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Gysling K
    (2012) Relevance of both type-1 and type-2 corticotropin releasing factor receptors in stress-induced relapse to cocaine seeking behaviour. Biochem Pharmacol 83:1–5.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Hahn J,
    2. Hopf FW, and
    3. Bonci A
    (2009) Chronic cocaine enhances corticotropin-releasing factor-dependent potentiation of excitatory transmission in ventral tegmental area dopamine neurons. J Neurosci 29:6535–6544.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Hauger RL,
    2. Olivares-Reyes JA,
    3. Braun S,
    4. Hernandez-Aranda J,
    5. Hudson CC,
    6. Gutknecht E,
    7. Dautzenberg FM, and
    8. Oakley RH
    (2013) Desensitization of human CRF2(a) receptor signaling governed by agonist potency and βarrestin2 recruitment. Regul Pept 186:62–76.
    OpenUrlCrossRef
  22. ↵
    1. Hauger RL,
    2. Risbrough V,
    3. Brauns O, and
    4. Dautzenberg FM
    (2006) Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets. CNS Neurol Disord Drug Targets 5:453–479.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Holmes KD,
    2. Babwah AV,
    3. Dale LB,
    4. Poulter MO, and
    5. Ferguson SS
    (2006) Differential regulation of corticotropin releasing factor 1alpha receptor endocytosis and trafficking by beta-arrestins and Rab GTPases. J Neurochem 96:934–949.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Kehne JH
    (2007) The CRF1 receptor, a novel target for the treatment of depression, anxiety, and stress-related disorders. CNS Neurol Disord Drug Targets 6:163–182.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Kim E and
    2. Sheng M
    (2004) PDZ domain proteins of synapses. Nat Rev Neurosci 5:771–781.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Kohout TA and
    2. Lefkowitz RJ
    (2003) Regulation of G protein-coupled receptor kinases and arrestins during receptor desensitization. Mol Pharmacol 63:9–18.
    OpenUrlFREE Full Text
  27. ↵
    1. Kostich WA,
    2. Chen A,
    3. Sperle K, and
    4. Largent BL
    (1998) Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: the CRF2gamma receptor. Mol Endocrinol 12:1077–1085.
    OpenUrlCrossRefPubMed
  28. ↵
    1. Kourrich S,
    2. Su T-P,
    3. Fujimoto M, and
    4. Bonci A
    (2012) The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci 35:762–771.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Kraetke O,
    2. Wiesner B,
    3. Eichhorst J,
    4. Furkert J,
    5. Bienert M, and
    6. Beyermann M
    (2005) Dimerization of corticotropin-releasing factor receptor type 1 is not coupled to ligand binding. J Recept Signal Transduct Res 25:251–276.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Liaw CW,
    2. Lovenberg TW,
    3. Barry G,
    4. Oltersdorf T,
    5. Grigoriadis DE, and
    6. de Souza EB
    (1996) Cloning and characterization of the human corticotropin-releasing factor-2 receptor complementary deoxyribonucleic acid. Endocrinology 137:72–77.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Liebsch G,
    2. Landgraf R,
    3. Engelmann M,
    4. Lörscher P, and
    5. Holsboer F
    (1999) Differential behavioural effects of chronic infusion of CRH 1 and CRH 2 receptor antisense oligonucleotides into the rat brain. J Psychiatr Res 33:153–163.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Magalhaes AC,
    2. Dunn H, and
    3. Ferguson SS
    (2012) Regulation of GPCR activity, trafficking and localization by GPCR-interacting proteins. Br J Pharmacol 165:1717–1736.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Magalhaes AC,
    2. Holmes KD,
    3. Dale LB,
    4. Comps-Agrar L,
    5. Lee D,
    6. Yadav PN,
    7. Drysdale L,
    8. Poulter MO,
    9. Roth BL,
    10. Pin JP,
    11. et al.
    (2010) CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling. Nat Neurosci 13:622–629.
    OpenUrlCrossRefPubMed
  34. ↵
    1. McLatchie LM,
    2. Fraser NJ,
    3. Main MJ,
    4. Wise A,
    5. Brown J,
    6. Thompson N,
    7. Solari R,
    8. Lee MG, and
    9. Foord SM
    (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393:333–339.
    OpenUrlCrossRefPubMed
  35. ↵
    1. Milan-Lobo L,
    2. Gsandtner I,
    3. Gaubitzer E,
    4. Rünzler D,
    5. Buchmayer F,
    6. Köhler G,
    7. Bonci A,
    8. Freissmuth M, and
    9. Sitte HH
    (2009) Subtype-specific differences in corticotropin-releasing factor receptor complexes detected by fluorescence spectroscopy. Mol Pharmacol 76:1196–1210.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. Müller MB,
    2. Zimmermann S,
    3. Sillaber I,
    4. Hagemeyer TP,
    5. Deussing JM,
    6. Timpl P,
    7. Kormann MS,
    8. Droste SK,
    9. Kühn R,
    10. Reul JM,
    11. et al.
    (2003) Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci 6:1100–1107.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Murat B,
    2. Devost D,
    3. Andrés M,
    4. Mion J,
    5. Boulay V,
    6. Corbani M,
    7. Zingg HH, and
    8. Guillon G
    (2012) V1b and CRHR1 receptor heterodimerization mediates synergistic biological actions of vasopressin and CRH. Mol Endocrinol 26:502–520.
    OpenUrlCrossRefPubMed
  38. ↵
    1. Navarro G,
    2. Quiroz C,
    3. Moreno-Delgado D,
    4. Sierakowiak A,
    5. McDowell K,
    6. Moreno E,
    7. Rea W,
    8. Cai NS,
    9. Aguinaga D,
    10. Howell LA,
    11. et al.
    (2015) Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine. J Neurosci 35:6639–6653.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Neve KA,
    2. Seamans JK, and
    3. Trantham-Davidson H
    (2004) Dopamine receptor signaling. J Recept Signal Transduct Res 24:165–205.
    OpenUrlCrossRefPubMed
  40. ↵
    1. O’Dowd BF,
    2. Ji X,
    3. Alijaniaram M,
    4. Rajaram RD,
    5. Kong MM,
    6. Rashid A,
    7. Nguyen T, and
    8. George SR
    (2005) Dopamine receptor oligomerization visualized in living cells. J Biol Chem 280:37225–37235.
    OpenUrlAbstract/FREE Full Text
  41. ↵
    1. Orozco-Cabal L,
    2. Liu J,
    3. Pollandt S,
    4. Schmidt K,
    5. Shinnick-Gallagher P, and
    6. Gallagher JP
    (2008) Dopamine and corticotropin-releasing factor synergistically alter basolateral amygdala-to-medial prefrontal cortex synaptic transmission: functional switch after chronic cocaine administration. J Neurosci 28:529–542.
    OpenUrlAbstract/FREE Full Text
  42. ↵
    1. Pal K,
    2. Swaminathan K,
    3. Xu HE, and
    4. Pioszak AA
    (2010) Structural basis for hormone recognition by the Human CRFR2alpha G protein-coupled receptor. J Biol Chem 285:40351–40361.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    1. Perry SJ,
    2. Junger S,
    3. Kohout TA,
    4. Hoare SR,
    5. Struthers RS,
    6. Grigoriadis DE, and
    7. Maki RA
    (2005) Distinct conformations of the corticotropin releasing factor type 1 receptor adopted following agonist and antagonist binding are differentially regulated. J Biol Chem 280:11560–11568.
    OpenUrlAbstract/FREE Full Text
  44. ↵
    1. Pin JP,
    2. Neubig R,
    3. Bouvier M,
    4. Devi L,
    5. Filizola M,
    6. Javitch JA,
    7. Lohse MJ,
    8. Milligan G,
    9. Palczewski K,
    10. Parmentier M,
    11. et al.
    (2007) International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the recognition and nomenclature of G protein-coupled receptor heteromultimers. Pharmacol Rev 59:5–13.
    OpenUrlAbstract/FREE Full Text
  45. ↵
    1. Rasmussen TN,
    2. Novak I, and
    3. Nielsen SM
    (2004) Internalization of the human CRF receptor 1 is independent of classical phosphorylation sites and of beta-arrestin 1 recruitment. Eur J Biochem 271:4366–4374.
    OpenUrlPubMed
  46. ↵
    1. Reul JM and
    2. Holsboer F
    (2002) Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Curr Opin Pharmacol 2:23–33.
    OpenUrlCrossRefPubMed
  47. ↵
    1. Roux BT and
    2. Cottrell GS
    (2014) G protein-coupled receptors: what a difference a ‘partner’ makes. Int J Mol Sci 15:1112–1142.
    OpenUrlCrossRefPubMed
  48. ↵
    1. Rozenfeld R and
    2. Devi LA
    (2010) Receptor heteromerization and drug discovery. Trends Pharmacol Sci 31:124–130.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Rutz C,
    2. Renner A,
    3. Alken M,
    4. Schulz K,
    5. Beyermann M,
    6. Wiesner B,
    7. Rosenthal W, and
    8. Schülein R
    (2006) The corticotropin-releasing factor receptor type 2a contains an N-terminal pseudo signal peptide. J Biol Chem 281:24910–24921.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Schulz K,
    2. Rutz C,
    3. Westendorf C,
    4. Ridelis I,
    5. Vogelbein S,
    6. Furkert J,
    7. Schmidt A,
    8. Wiesner B, and
    9. Schülein R
    (2010) The pseudo signal peptide of the corticotropin-releasing factor receptor type 2a decreases receptor expression and prevents Gi-mediated inhibition of adenylyl cyclase activity. J Biol Chem 285:32878–32887.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    1. Shaham Y,
    2. Erb S,
    3. Leung S,
    4. Buczek Y, and
    5. Stewart J
    (1998) CP-154,526, a selective, non-peptide antagonist of the corticotropin-releasing factor1 receptor attenuates stress-induced relapse to drug seeking in cocaine- and heroin-trained rats. Psychopharmacology (Berl) 137:184–190.
    OpenUrlCrossRefPubMed
  52. ↵
    1. Slater PG,
    2. Cerda CA,
    3. Pereira LA,
    4. Andrés ME, and
    5. Gysling K
    (2016b) CRF binding protein facilitates the presence of CRF type 2α receptor on the cell surface. Proc Natl Acad Sci USA 113:4075–4080.
    OpenUrlAbstract/FREE Full Text
  53. ↵
    1. Slater PG,
    2. Noches V, and
    3. Gysling K
    (2016a) Corticotropin-releasing factor type-2 receptor and corticotropin-releasing factor-binding protein coexist in rat ventral tegmental area nerve terminals originated in the lateral hypothalamic area. Eur J Neurosci 43:220–229.
    OpenUrlCrossRefPubMed
  54. ↵
    1. Sotomayor-Zárate R,
    2. Abarca J,
    3. Araya KA,
    4. Renard GM,
    5. Andrés ME, and
    6. Gysling K
    (2015) Exposure to repeated immobilization stress inhibits cocaine-induced increase in dopamine extracellular levels in the rat ventral tegmental area. Pharmacol Res 101:116–123.
    OpenUrlCrossRef
  55. ↵
    1. Szafran K,
    2. Faron-Górecka A,
    3. Kolasa M,
    4. Kuśmider M,
    5. Solich J,
    6. Zurawek D, and
    7. Dziedzicka-Wasylewska M
    (2013) Potential role of G protein-coupled receptor (GPCR) heterodimerization in neuropsychiatric disorders: a focus on depression. Pharmacol Rep 65:1498–1505.
    OpenUrlCrossRef
  56. ↵
    1. Tan H,
    2. Zhong P, and
    3. Yan Z
    (2004) Corticotropin-releasing factor and acute stress prolongs serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons. J Neurosci 24:5000–5008.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    1. Tanoue A,
    2. Ito S,
    3. Honda K,
    4. Oshikawa S,
    5. Kitagawa Y,
    6. Koshimizu TA,
    7. Mori T, and
    8. Tsujimoto G
    (2004) The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions. J Clin Invest 113:302–309.
    OpenUrlCrossRefPubMed
  58. ↵
    1. Teichmann A,
    2. Gibert A,
    3. Lampe A,
    4. Grzesik P,
    5. Rutz C,
    6. Furkert J,
    7. Schmoranzer J,
    8. Krause G,
    9. Wiesner B, and
    10. Schülein R
    (2014) The specific monomer/dimer equilibrium of the corticotropin-releasing factor receptor type 1 is established in the endoplasmic reticulum. J Biol Chem 289:24250–24262.
    OpenUrlAbstract/FREE Full Text
  59. ↵
    1. Teichmann A,
    2. Rutz C,
    3. Kreuchwig A,
    4. Krause G,
    5. Wiesner B, and
    6. Schülein R
    (2012) The Pseudo signal peptide of the corticotropin-releasing factor receptor type 2A prevents receptor oligomerization. J Biol Chem 287:27265–27274.
    OpenUrlAbstract/FREE Full Text
  60. ↵
    1. Terrillon S and
    2. Bouvier M
    (2004) Roles of G-protein-coupled receptor dimerization. EMBO Rep 5:30–34.
    OpenUrlAbstract/FREE Full Text
  61. ↵
    1. Ungless MA,
    2. Singh V,
    3. Crowder TL,
    4. Yaka R,
    5. Ron D, and
    6. Bonci A
    (2003) Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons. Neuron 39:401–407.
    OpenUrlCrossRefPubMed
  62. ↵
    1. Valdenaire O,
    2. Giller T,
    3. Breu V,
    4. Gottowik J, and
    5. Kilpatrick G
    (1997) A new functional isoform of the human CRF2 receptor for corticotropin-releasing factor. Biochim Biophys Acta 1352:129–132.
    OpenUrlPubMed
  63. ↵
    1. Walther C,
    2. Caetano FA,
    3. Dunn HA, and
    4. Ferguson SS
    (2015) PDZK1/NHERF3 differentially regulates corticotropin-releasing factor receptor 1 and serotonin 2A receptor signaling and endocytosis. Cell Signal 27:519–531.
    OpenUrlCrossRefPubMed
  64. ↵
    1. Wang B,
    2. Shaham Y,
    3. Zitzman D,
    4. Azari S,
    5. Wise RA, and
    6. You ZB
    (2005) Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking. J Neurosci 25:5389–5396.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    1. Wang B,
    2. You ZB,
    3. Rice KC, and
    4. Wise RA
    (2007) Stress-induced relapse to cocaine seeking: roles for the CRF(2) receptor and CRF-binding protein in the ventral tegmental area of the rat. Psychopharmacology (Berl) 193:283–294.
    OpenUrlCrossRefPubMed
  66. ↵
    1. Wang B,
    2. You ZB, and
    3. Wise RA
    (2009) Reinstatement of cocaine seeking by hypocretin (orexin) in the ventral tegmental area: independence from the local corticotropin-releasing factor network. Biol Psychiatry 65:857–862.
    OpenUrlCrossRefPubMed
  67. ↵
    1. Waselus M,
    2. Nazzaro C,
    3. Valentino RJ, and
    4. Van Bockstaele EJ
    (2009) Stress-induced redistribution of corticotropin-releasing factor receptor subtypes in the dorsal raphe nucleus. Biol Psychiatry 66:76–83.
    OpenUrlCrossRefPubMed
  68. ↵
    1. White JH,
    2. Wise A,
    3. Main MJ,
    4. Green A,
    5. Fraser NJ,
    6. Disney GH,
    7. Barnes AA,
    8. Emson P,
    9. Foord SM, and
    10. Marshall FH
    (1998) Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature 396:679–682.
    OpenUrlCrossRefPubMed
  69. ↵
    1. Williams CL,
    2. Buchta WC, and
    3. Riegel AC
    (2014) CRF-R2 and the heterosynaptic regulation of VTA glutamate during reinstatement of cocaine seeking. J Neurosci 34:10402–10414.
    OpenUrlAbstract/FREE Full Text
  70. ↵
    1. Wood SK,
    2. Zhang XY,
    3. Reyes BA,
    4. Lee CS,
    5. Van Bockstaele EJ, and
    6. Valentino RJ
    (2013) Cellular adaptations of dorsal raphe serotonin neurons associated with the development of active coping in response to social stress. Biol Psychiatry 73:1087–1094.
    OpenUrlCrossRefPubMed
  71. ↵
    1. Wootten D,
    2. Lindmark H,
    3. Kadmiel M,
    4. Willcockson H,
    5. Caron KM,
    6. Barwell J,
    7. Drmota T, and
    8. Poyner DR
    (2013) Receptor activity modifying proteins (RAMPs) interact with the VPAC2 receptor and CRF1 receptors and modulate their function. Br J Pharmacol 168:822–834.
    OpenUrlCrossRefPubMed
  72. ↵
    1. Young SF,
    2. Griffante C, and
    3. Aguilera G
    (2007) Dimerization between vasopressin V1b and corticotropin releasing hormone type 1 receptors. Cell Mol Neurobiol 27:439–461.
    OpenUrlCrossRefPubMed
  73. ↵
    1. Zorrilla EP,
    2. Logrip ML, and
    3. Koob GF
    (2014) Corticotropin releasing factor: a key role in the neurobiology of addiction. Front Neuroendocrinol 35:234–244.
    OpenUrlCrossRefPubMed
View Abstract
Back to top

In this issue

Download PDF
Article Alerts
Email Article
Citation Tools
Research ArticleMinireview—A Latin American Perspective On G Protein-Coupled Receptors

CRF Receptor’s Interacting Proteins

Paula G. Slater, Hector E. Yarur and Katia Gysling
Molecular Pharmacology November 1, 2016, 90 (5) 627-632; DOI: https://doi.org/10.1124/mol.116.104927
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section