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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

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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
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