Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • Log out
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • Log out
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Review ArticleMINIREVIEW

Calmodulin-Regulated Adenylyl Cyclases: Cross-Talk and Plasticity in the Central Nervous System

Hongbing Wang and Daniel R. Storm
Molecular Pharmacology March 2003, 63 (3) 463-468; DOI: https://doi.org/10.1124/mol.63.3.463
Hongbing Wang
Department of Pharmacology, University of Washington, Seattle, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel R. Storm
Department of Pharmacology, University of Washington, Seattle, Washington
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

Gene disruption studies have shown that the Ca2+-stimulated adenylyl cyclases, AC1 and AC8, are critical for some forms of synaptic plasticity, including long-term potentiation as well as long-term memory formation (LTM). It is hypothesized that these enzymes are required for LTM to support the increased expression of a family of genes regulated through the cAMP/Ca2+ response element-binding protein/cAMP response element transcriptional pathway. In contrast to AC1 and AC8, AC3 is a Ca2+-inhibited adenylyl cyclase that plays an essential role in olfactory signal transduction. Coupling of odorant receptors to AC3 stimulates cAMP transients that function as the major second messenger for olfactory signaling. These cAMP transients are caused, at least in part, by Ca2+ inhibition of AC3, which is mediated through calmodulin-dependent protein kinase II. The unique structure and regulatory properties of these adenylyl cyclases make them attractive drug target sites for modulation of a number of physiological processes including memory formation and olfaction.

Cross-talk between the cAMP signal transduction system and other signaling pathways is important for several forms of neuroplasticity, including long-term potentiation (LTP) and memory formation. The Ca2+-regulated adenylyl cyclases are important for adaptive changes in neurons because they provide a critical linkage between Ca2+ and cAMP signaling. This review focuses on the physiological roles of three Ca2+-regulated adenylyl cyclases, AC1, AC3, and AC8. AC1 and AC8 are Ca2+/CaM-stimulated enzymes, whereas Ca2+ inhibits AC3. Gene disruption studies have revealed that these enzymes play critical roles in several physiological processes, including olfaction, development of the sensory motor cortex, and hippocampus-dependent memory formation.

Distribution and Regulatory Properties of AC1

The existence of distinct forms of Ca2+-sensitive and -insensitive adenylyl cyclases was first demonstrated using CaM-Sepharose affinity chromatography (Westcott et al., 1979). Partially purified adenylyl cyclase from bovine brain was resolved into two forms: a Ca2+/CaM stimulated activity and a CaM-insensitive activity. In addition, polyclonal antibodies that distinguish between CaM-sensitive and -insensitive adenylyl cyclases in brain were isolated (Rosenberg and Storm, 1987). CaM-stimulated adenylyl cyclase was subsequently purified extensively using either CaM-Sepharose affinity chromatography (Yeager et al., 1985) or forskolin-Sepharose affinity chromatography (Pfeuffer et al., 1985;Smigel, 1986). The availability of purified adenylyl cyclase led to the isolation of a cDNA clone encoding AC1 (Krupinski et al., 1989).

Although the sequence of AC1 and other adenylyl cyclases predicts a membrane topology reminiscent of transporters or ion channels, there is no evidence that these enzymes function as membrane transporters or channels. However, it is interesting that cultured neurons express a voltage-sensitive adenylyl cyclase activity that is Ca2+-independent (Reddy et al., 1995). This suggests the interesting possibility that neurons contain an adenylyl cyclase that is sensitive to the membrane potential or that an adenylyl cyclase is associated with a regulatory protein that is sensitive to the membrane potential.

Of the adenylyl cyclase genes cloned, AC1 is the only neurospecific adenylyl cyclase identified thus far; it is expressed in brain, adrenal medulla, and retina (Xia et al., 1993). AC1 mRNA is expressed in the hippocampus (dentate gyrus, CA1-CA3), neocortex, entorhinal cortex, cerebellar cortex, and the olfactory system as well as the pineal (Xia et al., 1991; Tzavara et al., 1996). In monkey brain, AC1 protein is detectable in the mossy fibers as well as the molecular layers of both the dentate gyrus and fields CA1, CA2, and CA3 of the hippocampus (Kumar et al., 2001). Because AC1 is neurospecific, it provides a “pharmacological window of opportunity” to increase cAMP in specific areas of brain without the side affects associated with cAMP increases in other tissues.

AC1 is directly stimulated by Ca2+ and CaM in vivo (Choi et al., 1992a; Wu et al., 1993) with half-maximal stimulation at 150 to 200 nM free Ca2+, concentrations just above resting free Ca2+ in neurons. Several point mutations within the CaM binding domain of AC1 were made to determine whether its Ca2+sensitivity can be modified by mutagenesis and to verify assignment of the CaM binding domain. Replacement of Lys-504 with Asp causes a 4-fold decrease in sensitivity to Ca2+. Ca2+ and CaM stimulation are abolished by substitution of Phe-503 with Arg-503. Stimulation of AC1 activity in vivo by intracellular Ca2+ is also greatly diminished with the Arg-503 mutant. This indicates that Ca2+ stimulation of the enzyme in vivo is caused primarily by direct interactions with CaM and Ca2+. Direct interaction between the catalytic subunit of the adenylyl cyclase and CaM was also demonstrated by125I-CaM gel overlays (Minocherhomjee et al., 1987).

Although AC1 is not stimulated by activation of Gs-coupled receptors alone, it is stimulated by receptor activation when paired with Ca2+(Wayman et al., 1994). Consequently, AC1 is synergistically stimulated by Ca2+ and β-adrenergic agonist and functions as a coincidence factor to integrate Ca2+ and receptor-mediated signals. AC1 is inhibited by Gi-coupled receptors, including somatostatin and dopamine D2 receptors (Nielsen et al., 1996). It is also inhibited by CaM kinase IV in vivo (Wayman et al., 1996). The enzyme has two CaM kinase IV consensus phosphorylation sequences near its CaM binding domain at Ser-545 and Ser-552. Conversion of either serine to alanine by mutagenesis abolishes CaM kinase IV inhibition of AC1, suggesting that the activity of this enzyme may be directly inhibited by CaM kinase IV phosphorylation. These inhibitory constraints on AC1 activity may be required to prevent spurious cAMP increases caused by Ca2+ transients and to insure a significant signaling differential. Because synaptic plasticity may depend upon optimal cAMP levels, or transient cAMP increases, mechanisms for attenuation of AC1 may be just as important as stimulatory mechanisms.

Distribution and Properties of AC8

Although AC8 is expressed in brain, it is not neurospecific and is found in other tissues, including lung (Muglia et al., 1999) and parotid gland (Watson et al., 2000). In brain, the highest levels of AC8 mRNA are within the olfactory bulb, thalamus, habenula, cerebral cortex, and hypothalamic supraoptic and paraventricular nuclei. AC8 is also expressed in the hippocampus and cerebellum. AC8 is stimulated by CaM but its Ca2+ sensitivity is approximately 5-fold lower than AC1 (half-maximal activation by Ca2+ is 150 nM for AC1 and 800 nM for AC8) (Nielsen et al., 1996). The Ca2+ activation curve for adenylyl cyclase activity in hippocampal membrane preparations reflects the presence of a mixture of AC1 and AC8. The CaM binding domain of AC8, which is localized to the C-terminal end of AC8, resembles an IQ domain. Interestingly, IQ domains generally mediate Ca2+-inhibited or Ca2+-independent binding of proteins to CaM (Alexander et al., 1988). Studies with the P/Q-type calcium channels suggested a novel Ca2+-dependent calmodulin binding site in AC8 (Lee et al., 1999). The C-terminal region of AC8 shares significant sequence similarity to the novel CaM binding domain in α1A subunit of P/Q-type calcium channels. Peptides corresponding to the CaM binding domain in AC8 and α1A subunit inhibited calmodulin stimulation of AC8 activity (S. Wong and D. R. Storm, unpublished data). In another line, Gu and Cooper showed that the IQ domain in the C terminus of AC8 interacted with CaM and modulate Ca2+ stimulation (Gu and Cooper, 1999). Like AC1, AC8 is not stimulated by Gs-coupled receptors in vivo (Nielsen et al., 1996), even though it is stimulated by GS-α complexed to guanosine 5′-O-(3-thio)triphosphate in vitro (Cali et al., 1994). In contrast to AC1, AC8 is not synergistically stimulated by Gs-coupled receptors and Ca2+ in vivo. Although serotonin stimulates AC8 activity in vivo, this stimulation is mediated by serotonin-induced increases in intracellular Ca2+ (Baker et al., 1998). AC8 is not inhibited by Gi-coupled receptors in vivo or by CaM kinase IV; it is a pure Ca2+ detector that responds to relatively high concentrations of Ca2+ compared with AC1.

Distribution and Regulatory Properties of AC3

Although AC3 is expressed in a number of tissues including heart, vascular smooth muscle, germ cells, brain, and lung (Xia et al., 1992;Defer et al., 1998; Ishikawa et al., 2000), it was first discovered in the olfactory epithelium (Bakalyar and Reed, 1990). AC3 in membrane preparations is stimulated by Ca2+ and CaM, when it is concomitantly activated by Gs (Choi et al., 1992b). However, submicromolar concentrations of intracellular free Ca2+ inhibit receptor-stimulated AC3, suggesting that it may be inhibited by a Ca2+-stimulated kinase (Wayman et al., 1995b). Indeed, CaM kinase inhibitors antagonize Ca2+ inhibition of AC3 and coexpression of constitutively activate CaM kinase II completely inhibits isoproterenol-stimulated AC3 activity. Furthermore, AC3 is phosphorylated in human embryonic kidney-293 cells when intracellular Ca2+ is increased. This phosphorylation is prevented by CaM-kinase inhibitors (Wei et al., 1996). Site-directed mutagenesis of a CaM-kinase II consensus site (Ser-1076 to Ala-1076) in AC3 blocks Ca2+-stimulated phosphorylation and inhibition of AC3 in vivo. Cells expressing AC3 exhibit hormone-stimulated Ca2+ and cAMP oscillations. Activation of AC3 by hormones through G protein increases cAMP level and stimulates PKA activity. Consequently, PKA phosphorylates and activates inositol trisphosphate receptors, which are responsible for Ca2+ release from internal pool. This leads to activation of CaMKII and inhibition of AC3, and intracellular cAMP level drops because of cAMP phosphodiesterase activity. Once cAMP level decreases below a certain threshold point, the inositol trisphosphate receptors are dephosphorylated, and Ca2+ gets resequestered (Wayman et al., 1995a). Consequently, cAMP and Ca2+ will continue to oscillate as long as an adenylyl cyclase activator stimulates the enzyme. Ca2+ oscillations in cells expressing AC3 show a periodicity of 3 to 5 min. The distribution and regulatory properties of AC1, AC3, and AC8 are summarized in Table1.

View this table:
  • View inline
  • View popup
Table 1

Distribution and regulatory properties of Ca2+-sensitive adenylyl cyclases

AC1 is the Gatekeeper for Pineal Melatonin Synthesis

The circadian organization of behavior determines how complex organisms respond to social and light/dark cues encountered on a daily and seasonal basis. The daily cycle of melatonin synthesis in the pineal is controlled by the circadian clock in the suprachiasmatic nucleus (Chang and Reppert, 2001; Dunlap, 1999). Melatonin biosynthesis in the pineal gland is regulated by cAMP, which stimulates transcription of genes encoding enzymes important for circadian expression of melatonin (Borjigin et al., 1995).

Stimulation of adenylyl cyclase activity in the pineal in response to activation of β- and α1-adrenergic agonists suggest that AC1 plays a major role in generating cAMP signals in response to nocturnal norepinephrine. Increases in pineal intracellular cAMP caused by activation of β-adrenergic receptors are greatly enhanced by costimulation of α1-adrenergic receptors (Vanecek et al., 1985). Because activation of α1-adrenergic receptors increases intracellular Ca2+, this cAMP increase is very probably caused by synergistic stimulation of AC1 by Ca2+ and β-adrenergic receptors (Wayman et al., 1994). Ca2+-stimulated adenylyl cyclase activity in the pineal shows a circadian oscillation with maximal levels during subjective night (Tzavara et al., 1996). On the other hand, AC1 mRNA shows maximum expression at midday with a minimum at night; synthesis of mRNA for AC1 and translation to protein are separated by 12 h. An analysis of the promoter for the AC1 gene provides an explanation for the circadian expression of AC1 mRNA (Chan et al., 2001). A 280-bp fragment from the AC1 promoter region that contains the transcription start site directs reporter gene expression in cultured pinealocytes and CNS neurons. Interestingly, pinealocyte expression of the reporter gene is inhibited by increases in cAMP. This cAMP-inhibitable element may explain why AC1 mRNA in the pineal gland is low at night, when cAMP is elevated, and high during the day, when cAMP signals drop.

Calcium-Stimulated Adenylyl Cyclase Activity is Critical for Hippocampus Dependent Long-Term Memory and Synaptic Plasticity

The physiological roles of Ca2+-stimulated adenylyl cyclases have been evaluated by generation of AC1−/− mice (Wu et al., 1995), AC8−/− mice (Wong et al., 1999; Schaefer et al., 2000; Watson et al., 2000), and AC1−/− × AC8−/− double knockout mice (Wong et al., 1999). AC1−/− mice have normal growth, motor coordination, and longevity. They show no detectable anatomical or morphological differences in the brain except that they lack barrel patterning in the sensory motor cortex (Abdel-Majid et al., 1998). Compared with wild-type mice, Ca2+-sensitive adenylyl cyclase activities in the hippocampus and cerebellum are decreased approximately 50% in AC1−/− mice. Because there are comparable levels of AC1 and AC8 in the hippocampus, this indicates that there are not compensating increases in AC8 to adjust for the loss of AC1. Similar observations have been made with AC8 mutant mice; there is no compensating increase in AC1 with AC8−/− mice. Membranes isolated from the hippocampus of AC1−/− × AC8−/− mice show no Ca2+-stimulated adenylyl cyclase activity (Wong et al., 1999).

AC1−/− Mice Exhibit Defects in Several Types of LTP

Although they exhibit long-lasting LTP (L-LTP) in area CA1 of the hippocampus that persists for greater than 3 h, there are quantitative differences between the mutant and wild-type mice (Wu et al., 1995). For example, the rate of increase of the excitatory postsynaptic potential slope in hippocampal slices from the mutant mice is half that of the wild-type mice. The maximal field excitatory postsynaptic potential slope above baseline is also significantly reduced in mutant mice. In contrast to NMDA receptor-dependent LTP in area CA1, which is dependent upon increased postsynaptic Ca2+, mossy fiber LTP requires an increase in presynaptic Ca2+ (Zalutsky and Nicoll, 1990;Johnston et al., 1992). Evidence from several laboratories suggests that PKA activation is obligatory for the induction and maintenance of mossy fiber LTP (Weisskopf et al., 1994; Huang and Kandel, 1996), and it is hypothesized that mossy fiber LTP is caused by stimulation of an adenylyl cyclase by presynaptic Ca2+ increases (Weisskopf et al., 1994; Villacres et al., 1998). Subsequent activation of PKA may stimulate prolonged glutamate release. To test this hypothesis, mossy fiber LTP was examined in AC1−/− mice. Although the mutant mice exhibit normal paired pulse facilitation, mossy fiber LTP is significantly impaired in AC1 −/− mice. High concentrations of forskolin induce mossy fiber LTP to comparable levels in wild-type and AC1 mutant mice. This indicates that signaling components downstream from the adenylyl cyclase, including PKA, ion channels, and secretory machinery, are not affected by disruption of the AC1 gene. These data indicate that coupling of Ca2+ to activation of AC1 is crucial for mossy fiber LTP, most likely through activation of PKA and enhancement of excitatory amino acid secretion (Trudeau et al., 1996; Castillo et al., 1997; Geppert et al., 1997). Because there are noradrenergic projections from the locus ceruleus to the dentate gyrus and to the stratum lucidum of the CA3, where the glutamatergic mossy fibers terminate, modulation of mossy fiber LTP by β-adrenergic input (Huang and Kandel, 1996) may be attributable to synergistic stimulation of AC1 by β-adrenergic receptors and Ca2+.

The presynaptic LTP mechanism described above may not be unique to the mossy fiber/CA3 synapse. AC1 is expressed at relatively high levels in cerebellar granule cells (Xia et al., 1991). Cerebellar parallel fibers exhibit an LTP with properties similar to hippocampal mossy fiber LTP (Salin et al., 1996). It is independent of NMDA receptors but dependent on extracellular Ca2+ and adenylyl cyclase activation. Interestingly, AC1−/− mice show a number of defects in cerebellar physiology, including the complete lack of parallel fiber/Purkinje cell LTP induced by 4- to 8-Hz parallel fiber stimulation (Storm et al., 1998; Lev-Ram et al., 2002). This blockade is not accompanied by alterations in a number of basal electrophysiological parameters and is bypassed by application of an exogenous cAMP analog, suggesting that it results specifically from deletion of AC1. However, cerebellar LTP induced by 1 Hz parallel fiber stimulation for at least 300 s is not reduced in AC1−/− mutant mice (Lev-Ram et al., 2002).

AC1−/− mice show normal LTM for several forms of fear-associated learning including contextual, passive avoidance, and cued training. However, they do not show normal spatial memory when examined in the Morris water task, a test that measures the ability of a mouse to navigate by means of direct and indirect visual cues (Wu et al., 1995). Although AC1−/− mice learn to find the hidden platform in the Morris water task as well as wild-type mice, they do not show a preference for the region where the platform was during training. This suggests that AC1 may be important for spatial memory.

Because AC1−/− and AC8−/− mice both exhibit L-LTP as well as fear-associated learning and memory, transgenic mice were prepared that lacked both AC1 and AC8 (AC1−/− × AC8−/− mice). Although the single mutants exhibit normal LTM for contextual and passive avoidance learning, the AC1−/− × AC8−/− mice do not (Wong et al., 1999). However, AC1−/− × AC8−/− mice are able to learn and exhibit short-term memory that lasts only 5 to 10 min after training (Fig.1). This indicates that the AC1−/− × AC8−/− mice are memory mutants but learn normally and with normal short-term memory. To determine whether this defect in passive avoidance LTM is caused by a loss of cAMP increases in the hippocampus, AC1−/− × AC8−/− mutant mice were unilaterally cannulated to administer forskolin, an adenylyl cyclase activator. Administration of forskolin to area CA1 of the hippocampus 15 min before training restores normal memory for passive avoidance learning. The defect in L-LTP is also reversed by application of forskolin to AC1−/−× AC8−/− hippocampal slices. These data indicate that Ca2+-stimulated adenylyl cyclase activity is essential for L-LTP as well as some forms of LTM and that either AC1 or AC8 can produce the critical cAMP signal.

Figure 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1

Mice lacking both AC1 and AC8 have short-term memory but show memory loss within 30 min after training for passive avoidance learning and memory. During passive avoidance training, mice are placed into a chamber that has lighted and dark sides. Mice have a natural tendency to crossover into the dark chamber. During training, mice were shocked when they crossed over to the dark. Memory for passive avoidance training is manifested as an increase in the crossover latency when they are placed into the training chamber later. Wild type (n = 9) and AC1−/− × AC8−/− (n = 14) mutant mice were submitted to passive avoidance training and analyzed for memory at 5 and 30 min. AC1−/− × AC8−/− mice exhibit comparable crossover latencies at 5 min, whereas they exhibit a significant deficit in passive avoidance memory at 30 min.

Why is Ca2+-stimulated adenylyl cyclase activity required for LTM? Transcriptionally dependent L-LTP in area CA1 of the hippocampus and hippocampus-dependent LTM are initiated by activation of NMDA receptors and postsynaptic Ca2+increases. Both of these processes depend on cAMP signaling and de novo transcription. The transcriptional pathway most strongly implicated in LTM formation is the CREB/CRE-transcriptional pathway (Athos et al., 2002; Bourtchuladze et al., 1994; Impey et al., 1998b; Pittenger et al., 2002). It is hypothesized that long-term increases in synaptic plasticity and LTM depend, at least in part, on increased transcription of a family of genes regulated through CREs in their promoters. Ca2+ increases generated through NMDA receptors stimulate CRE-mediated transcription in the hippocampus by stimulating Erk/MAP kinase, CaM-stimulated adenylyl cyclases, and CaM kinase IV (Fig. 2). The major Ca2+-stimulated CREB kinase in hippocampal neurons is rsk2, which is activated by Ca2+through the Erk/MAP kinase family, a process that requires the nuclear translocation of Erk/MAP kinase (Impey et al., 1998a). The nuclear translocation of Erk/MAP kinase depends upon a cAMP signal, which, we hypothesize, arises from CaM-stimulated adenylyl cyclases.

Figure 2
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2

Calmodulin-stimulated adenylyl cyclases provide a critical cAMP signal required to support Ca2+ activation of CRE-mediated transcription in the hippocampus. It is hypothesized that postsynaptic Ca2+ increases generated through NMDA receptors activate several signal transduction pathways including the Erk/MAP kinase and cAMP regulatory pathways. It is proposed that either AC1 or AC8 can provide the cAMP signal necessary for activation of CRE-mediated transcription for L-LTP and LTM. Convergence of these pathways at the level of the CREB/CRE transcriptional pathway may increase expression of a family of genes required for LTM.

AC1 Is Required for Development of the Mouse Somatosensory Cortex

The somatosensory cortex of mice contains a patterned distribution of neurons in layer IV termed the barrelfield (Woolsey and Van der Loos, 1970). Thalamocortical afferents terminating in layer IV are organized such that each barrel structure, a group of neurons surrounding a cell-sparse center, represents a specific receptive field. Mice homozygous for the barrelless (brl) mutation, a spontaneous mouse mutant, do not develop barrel structures in the somatosensory cortex even though the size of individual whisker representations is comparable with those wild-type mice (Welker et al., 1996). A genetic analysis revealed that the AC1 gene (Adcy1) is disrupted in brl mutant mice (Abdel-Majid et al., 1998), a discovery that was confirmed by showing that AC1 −/− mice are also barrelless. This was the first evidence that the cAMP signal transduction pathway is important for pattern formation in the brain. The specific role of AC1 for pattern formation has not been defined but is presumably dependent upon Ca2+ -stimulated cAMP increases in the somatosensory cortex.

AC3 is Required for Detection of Odorants in the Main Olfactory Epithelium

Many odorants stimulate cAMP levels in cilia preparations from the olfactory epithelium, and it has been hypothesized that cAMP is a major secondary messenger for olfaction (Pace et al., 1985; Pfeuffer et al., 1989). The main olfactory epithelium contains several adenylyl cyclases, including AC2, AC3, and AC4. To evaluate the role of AC3 for olfactory responses and to determine whether cAMP signaling is required for olfaction, the gene for AC3 was disrupted in mice (Wong et al., 2000). Interestingly, electro-olfactogram responses in the main olfactory bulb are completely ablated in AC3 mutants, despite the presence of AC2 and AC4 in olfactory cilia. Furthermore, AC3 mutants fail several odorant-based behavioral tests, indicating that AC3 and cAMP signaling are critical for olfactory-dependent behavior mediated through the main olfactory epithelium. This was the first direct evidence that cAMP signaling is required for olfaction.

Desensitization of olfactory signaling is a critical property of the olfactory system that allows animals to respond to odorants. An important feature of odorant-stimulated cAMP increases is their transient nature, which may be attributable, at least in part, to the unique regulatory properties of AC3. Because odorant-stimulated cAMP increases are accompanied by elevated intracellular Ca2+ (Tareilus et al., 1995), CaM kinase II inhibition of AC3 may contribute to termination of olfactory signaling. To test this hypothesis, phosphorylation of AC3 at Ser-1076 was monitored using a polyclonal antibody specific for AC3 phosphorylated at Ser-1076 (Wei et al., 1998). A brief exposure of olfactory cilia or primary olfactory neurons to odorants stimulates phosphorylation of AC3 at Ser-1076. This phosphorylation is blocked by inhibitors of CaM kinase II, which also ablate cAMP decreases associated with odorant-stimulated cAMP transients.

What is the physiological significance of multiple cAMP transients caused by odorants? An animal cannot sense an olfactory gradient unless it can turn off the olfactory signal and re-sample during movement through an odorant gradient. It is hypothesized that rodents may need multiple peaks of odorant-stimulated cAMP increases to detect odorant gradients. The initial rapid cAMP increase is crucial because it alerts the animal to the presence of a specific odorant in its environment. The animal may then react by moving toward or away from the odorant source, if and only if it can compare a second odorant signal within the time scale that it takes to move through a gradient. An animal may determine whether it is moving up a positive odorant gradient by comparing the amplitude of the first cAMP transient with subsequent signals.

Collectively, these data indicate that AC3 is ideally suited to couple odorant receptors to cAMP increases and to provide a mechanism that contributes to the rapid decline in intracellular cAMP. This general model is supported by data showing that treatment of olfactory sensory neurons with CaM kinase II inhibitors impairs odor adaptation (Leinders-Zufall et al., 1999).

Pharmacological Considerations

Although the catalytic subunits of AC have not received serious attention as drug target sites, the distinct properties and their different expression patterns make them worthy of consideration. A considerable body of evidence indicates that increases in cAMP are required for, or positively modulate, various forms of synaptic plasticity in the central nervous system. This suggest that drugs that increase cAMP in specific areas of brain in response to synaptic specific signaling may enhance synaptic plasticity and memory formation. AC1 is an attractive drug target site for this purpose because it is neurospecific and expressed in specific areas of brain important for learning and memory. Drugs that specifically enhance AC1 activity, only when it is activated by Ca2+, may be preferable to those that cause sustained increases in cAMP, such as inhibitors of the cyclic nucleotide phosphodiesterases. Because of the pivotal role played by AC3 in olfaction, it may be a useful drug target site for enhancement or inhibition of olfaction.

Footnotes

    • Received October 17, 2002.
    • Accepted December 20, 2002.
  • This work was supported by grants from the National Institutes of Health.

Abbreviations

LTP
long-term potentiation
LTM
long-term memory
CaM
calmodulin
IQ domain
protein motif mediating interaction with calmodulin, usually consisting of consensus sequence as IQXXXRGXXXR
CRE
cAMP/Ca2+ response element
CREB
cAMP/Ca2+ response element-binding protein
PKA
cAMP-dependent protein kinase
NMDA
N-methyl-d-aspartate
Erk/MAP
extracellular signal-regulated kinase/mitogen-activated protein
L-LTP
long-lasting long-term potentiation
  • The American Society for Pharmacology and Experimental Therapeutics

References

  1. ↵
    1. Abdel-Majid RM,
    2. Leong WL,
    3. Schalkwyk LC,
    4. Smallman DS,
    5. Wong ST,
    6. Storm DR,
    7. Fine A,
    8. Dobson MJ,
    9. Guernsey DL, and
    10. Neumann PE
    (1998) Loss of adenylyl cyclase I activity disrupts patterning of mouse somatosensory cortex. Nat Genet 19:289–291.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Alexander KA,
    2. Wakim BT,
    3. Doyle GS,
    4. Walsh KA, and
    5. Storm DR
    (1988) Identification and characterization of the calmodulin-binding domain of neuromodulin, a neurospecific calmodulin-binding protein. J Biol Chem 263:7544–7549.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Athos J,
    2. Impey S,
    3. Pineda V,
    4. Chen X, and
    5. Storm D
    (2002) Hippocampal CRE-mediated gene expression is required for contextual memory formation. Nature Neuroscience 5:1119–1120.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Bakalyar HA and
    2. Reed RR
    (1990) Identification of a specialized adenylyl cyclase that may mediate odorant detection. Science (Wash DC) 250:1403–1406.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Baker LP,
    2. Nielsen MD,
    3. Impey S,
    4. Metcalf MA,
    5. Poser SW,
    6. Chan G,
    7. Obrietan K,
    8. Hamblin MW, and
    9. Storm DR
    (1998) Stimulation of type 1 and type 8 Ca2+/calmodulin-sensitive adenylyl cyclases by the Gs-coupled 5-hydroxytryptamine subtype 5-HT7A receptor. J Biol Chem 273:17469–17476.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Borjigin J,
    2. Wang MM, and
    3. Snyder SH
    (1995) Diurnal variation in mRNA encoding serotonin N-acetyltransferase in pineal gland. Nature (Lond) 378:783–785.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Bourtchuladze R,
    2. Frenguelli B,
    3. Blendy J,
    4. Cioffi D,
    5. Schutz G, and
    6. Silva AJ
    (1994) Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79:59–68.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Cali JJ,
    2. Zwaagstra C,
    3. Mons N,
    4. Cooper DMF, and
    5. Krupinski J
    (1994) Type VIII adenylyl cyclase: a Ca2+/calmodulin stimulated enzyme expressed in discrete regions of rat brain. J Biol Chem 269:12190–12196.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Castillo PE,
    2. Janz R,
    3. Sudhof TC,
    4. Tzounopoulos T,
    5. Malenka RC, and
    6. Nicoll RA
    (1997) Rab3A is essential for mossy fibre long-term potentiation in the hippocampus. Nature (Lond) 388:590–593.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Chan GC,
    2. Lernmark U,
    3. Xia Z, and
    4. Storm DR
    (2001) DNA elements of the type 1 adenylyl cyclase gene locus enhance reporter gene expression in neurons and pinealocytes. Eur J Neurosci 13:2054–2066.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Chang DC and
    2. Reppert SM
    (2001) The circadian clocks of mice and men. Neuron 29:555–558.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Choi EJ,
    2. Wong ST,
    3. Hinds TR, and
    4. Storm DR
    (1992a) Calcium and muscarinic agonist stimulation of type I adenylyl cyclase in whole cells. J Biol Chem 267:12440–12442.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Choi EJ,
    2. Xia Z, and
    3. Storm DR
    (1992b) Stimulation of the type III olfactory adenylyl cyclase by calcium and calmodulin. Biochem 31:6492–6498.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Defer N,
    2. Marinx O,
    3. Poyard M,
    4. Lienard MO,
    5. Jegou B, and
    6. Hanoune J
    (1998) The olfactory adenylyl cyclase type 3 is expressed in male germ cells. FEBS Lett 424:216–220.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Dunlap JC
    (1999) Molecular bases for circadian clocks. Cell 96:271–290.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Geppert M,
    2. Goda Y,
    3. Stevens CF, and
    4. Sudhof TC
    (1997) Rab3A regulates a late step in synaptic vesicle fusion. Nature (Lond) 387:810–814.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Gu C and
    2. Cooper DM
    (1999) Calmodulin-binding sites on adenylyl cyclase type VIII. J Biol Chem 274:8012–8021.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Huang YY and
    2. Kandel ER
    (1996) Modulation of both the early and the late phase of mossy fiber LTP by the activation of beta-adrenergic receptors. Neuron 16:611–617.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Impey S,
    2. Obrietan K,
    3. Wong ST,
    4. Poser S,
    5. Yano S,
    6. Wayman G,
    7. Deloulme JC,
    8. Chan G, and
    9. Storm DR
    (1998a) Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21:869–83.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Impey S,
    2. Smith DM,
    3. Obrietan K,
    4. Donahue R,
    5. Wade C, and
    6. Storm DR
    (1998b) Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nature Neurosci 1:595–601.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Ishikawa Y,
    2. Grant BS,
    3. Okumura S,
    4. Schwencke C, and
    5. Yamamoto M
    (2000) Immunodetection of adenylyl cyclase protein in tissues. Mol Cell Endocrinol 162:107–112.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Johnston D,
    2. Williams S,
    3. Jaffee D, and
    4. Gray R
    (1992) NMDA-receptor-independent long-term potentiation. Annu Rev Physiol 54:489–505.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Krupinski J,
    2. Coussen F,
    3. Bakalyar HA,
    4. Tang WJ,
    5. Feinstein PG,
    6. Orth K,
    7. Slaughter C,
    8. Reed RR, and
    9. Gilman AG
    (1989) Adenylyl cyclase amino acid sequence: possible channel- or transporter-like structure. Science (Wash DC) 244:1558–1564.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Kumar PA,
    2. Baker LP,
    3. Storm DR, and
    4. Bowden DM
    (2001) Expression of type I adenylyl cyclase in intrinsic pathways of the hippocampal formation of the macaque (Macaca nemestrina). Neurosci Lett 299:181–184.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Lee A,
    2. Wong ST,
    3. Gallagher D,
    4. Li B,
    5. Storm DR,
    6. Scheuer T, and
    7. Catterall WA
    (1999) Ca2+/calmodulin binds to and modulates P/Q-type calcium channels. Nature (Lond) 399:155–159.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Leinders-Zufall T,
    2. Ma M, and
    3. Zufall F
    (1999) Impaired odor adaptation in olfactory receptor neurons after inhibition of Ca2+/Calmodulin kinase II. J Neurosci 19:1–6.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    1. Lev-Ram V,
    2. Wong ST,
    3. Storm DR, and
    4. Tsien RY
    (2002) A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP. Proc Natl Acad Sci USA 99:8389–8393.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Minocherhomjee M,
    2. Selfe S,
    3. Flowers NJ, and
    4. Storm DR
    (1987) Direct interaction between the catalytic subunit of the calmodulin-sensitive adenylate cyclase from bovine brain with 125I-labeled wheat germ agglutinin and 125I-labeled calmodulin. Biochem 26:4444–4448.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Muglia LM,
    2. Schaefer ML,
    3. Vogt SK,
    4. Gurtner G,
    5. Imamura A, and
    6. Muglia LJ
    (1999) The 5′-flanking region of the mouse adenylyl cyclase type VIII gene imparts tissue-specific expression in transgenic mice. J Neurosci 19:2051–2058.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Nielsen MD,
    2. Chan GCK,
    3. Poser SW, and
    4. Storm DR
    (1996) Differential regulation of type I and type VIII Calcium-stimulated adenylyl cyclases by G(i)-coupled receptors in vivo. J Biol Chem 271:33308–33316.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Pace U,
    2. Hanski E,
    3. Salomon Y, and
    4. Lancet D
    (1985) Odorant-sensitive adenylate cyclase may mediate olfactory reception. Nature (Lond) 316:255–258.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Pfeuffer E,
    2. Mollner S,
    3. Lancet D, and
    4. Pfeuffer T
    (1989) Olfactory adenylyl cyclase. J Biol Chem 264:18803–18807.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Pfeuffer E,
    2. Mollner S, and
    3. Pfeuffer T
    (1985) Adenylate cyclase from bovine brain cortex: purification and characterization of the catalytic unit. EMBO (Eur Mol Biol Organ) J 4:3675–3675.
    OpenUrlPubMed
  34. ↵
    1. Pittenger C,
    2. Huang YY,
    3. Paletzki RF,
    4. Bourtchouladze R,
    5. Scanlin H,
    6. Vronskaya S, and
    7. Kandel ER
    (2002) Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron 34:447–462.
    OpenUrlCrossRefPubMed
  35. ↵
    1. Reddy R,
    2. Smith D,
    3. Wayman G,
    4. Wu Z,
    5. Villacres EC, and
    6. Storm DR
    (1995) Voltage-sensitive adenylyl cyclase activity in cultured neurons. A calcium-independent phenomenon. J Biol Chem 270:14340–14346.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. Rosenberg GB and
    2. Storm DR
    (1987) Immunological distinction between calmodulin-sensitive and calmodulin-insensitive adenylate cyclases. J Biol Chem 262:7623–7628.
    OpenUrlAbstract/FREE Full Text
  37. ↵
    1. Salin PA,
    2. Malenka RC, and
    3. Nicoll RA
    (1996) Cyclic AMP mediates a presynaptic form of LTP at cerebellar parallel fiber synapses. Neuron 16:797–803.
    OpenUrlCrossRefPubMed
  38. ↵
    1. Schaefer ML,
    2. Wong ST,
    3. Wozniak DF,
    4. Muglia LM,
    5. Liauw JA,
    6. Zhuo M,
    7. Nardi A,
    8. Hartman RE,
    9. Vogt SK,
    10. Luedke CE,
    11. et al.
    (2000) Altered stress-induced anxiety in adenylyl cyclase type VIII-deficient mice. J Neurosci 20:4809–4820.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Smigel MD
    (1986) Purification of brain adenylyl cyclase using forskolin affinity chromatography and WGA-Sepharose. J Biol Chem 261:1976–1982.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    1. Storm DR,
    2. Hansel C,
    3. Hacker B,
    4. Parent A, and
    5. Linden DJ
    (1998) Impaired cerebellar LTP in type I adenylyl cyclase mutant mice. Neuron 20:1199–1210.
    OpenUrlCrossRefPubMed
  41. ↵
    1. Tareilus E,
    2. Noe J, and
    3. Breer H
    (1995) Calcium signals in olfactory neurons. Biochim Biophys Acta 1269:129–138.
    OpenUrlPubMed
  42. ↵
    1. Trudeau LE,
    2. Emery DG, and
    3. Haydon PG
    (1996) Direct modulation of the secretory machinery underlies PKA-dependent synaptic facilitation in hippocampal neurons. Neuron 17:789–797.
    OpenUrlCrossRefPubMed
  43. ↵
    1. Tzavara ET,
    2. Pouille Y,
    3. Defer N, and
    4. Hanoune J
    (1996) Diurnal variation of the adenylyl cyclase type 1 in the rat pineal gland. Proc Natl Acad Sci USA 93:11208–11212.
    OpenUrlAbstract/FREE Full Text
  44. ↵
    1. Vanecek J,
    2. Sugden D,
    3. Weller J, and
    4. Klein DC
    (1985) Atypical synergistic alpha 1- and beta-adrenergic regulation of adenosine 3′,5′-monophosphate and guanosine 3′,5′-monophosphate in rat pinealocytes. Endocrinology 116:2167–2173.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Villacres EC,
    2. Wong ST,
    3. Chavkin C, and
    4. Storm DR
    (1998) Type I adenylyl cyclase mutant mice have impaired mossy fiber long-term potentiation. J Neurosci 18:3186–3194.
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. Watson EL,
    2. Jacobson KL,
    3. Singh JC,
    4. Idzerda R,
    5. Ott SM,
    6. DiJulio DH,
    7. Wong ST, and
    8. Storm DR
    (2000) The Type 8 Adenylyl Cyclase Is Critical for Ca2+ Stimulation of cAMP Accumulation in Mouse Parotid Acini. J Biol Chem 275:14691–14699.
    OpenUrlAbstract/FREE Full Text
  47. ↵
    1. Wayman GA,
    2. Hinds TR, and
    3. Storm DR
    (1995a) Hormone stimulation of type III adenylyl cyclase causes Ca2+ oscillations in HEK-293 cells. J Biol Chem 270:24108–24115.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    1. Wayman GA,
    2. Impey S, and
    3. Storm DR
    (1995b) Ca2+ inhibition of type III adenylyl cyclase in vivo. J Biol Chem 270:21480–21486.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Wayman GA,
    2. Impey S,
    3. Wu Z,
    4. Kindsvogel W,
    5. Prichard L, and
    6. Storm DR
    (1994) Synergistic activation of the type I adenylyl cyclase by Ca2+ and Gs-coupled receptors in vivo. J Biol Chem 269:25400–5.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Wayman GA,
    2. Wei J,
    3. Wong S, and
    4. Storm DR
    (1996) Regulation of type I adenylyl cyclase by calmodulin kinase IV in vivo. Mol Cell Biol 16:6075–6082.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    1. Wei J,
    2. Wayman G, and
    3. Storm DR
    (1996) Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. J Biol Chem 271:24231–24235.
    OpenUrlAbstract/FREE Full Text
  52. ↵
    1. Wei J,
    2. Zhao AZ,
    3. Chan GC,
    4. Baker LP,
    5. Impey S,
    6. Beavo JA, and
    7. Storm DR
    (1998) Phosphorylation and inhibition of olfactory adenylyl cyclase by CaM kinase II in Neurons: a mechanism for attenuation of olfactory signals. Neuron 21:495–504.
    OpenUrlCrossRefPubMed
  53. ↵
    1. Weisskopf MG,
    2. Castillo PE,
    3. Zalutsky RA, and
    4. Nicoll RA
    (1994) Mediation of hippocampal mossy fiber long-term potentiation by cyclic AMP. Science (Wash DC) 23:1878–1882.
    OpenUrl
  54. ↵
    1. Welker E,
    2. Armstrong-James M,
    3. Bronchti G,
    4. Ourednik W,
    5. Gheorghita-Baechler F,
    6. Dubois R,
    7. Guernsey DL,
    8. Van der Loos H, and
    9. Neumann PE
    (1996) Altered sensory processing in the somatosensory cortex of the mouse mutant barrelless. Science (Wash DC) 271:1864–1867.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    1. Westcott KR,
    2. LaPorte DC, and
    3. Storm DR
    (1979) Resolution of adenylyl cyclase sensitive and insensitive to Ca2+ and CDR by CDR-Sepharose affinity chromatography. Proc Natl Acad Sci USA 76:204–228.
    OpenUrlAbstract/FREE Full Text
  56. ↵
    1. Wong ST,
    2. Athos J,
    3. Figueroa XA,
    4. Pineda VV,
    5. Schaefer ML,
    6. Chavkin CC,
    7. Muglia LJ, and
    8. Storm DR
    (1999) Calcium-stimulated adenylyl cyclase activity is critical for hippocampus dependent long-term memory and late-phase LTP. Neuron 23:787–798.
    OpenUrlCrossRefPubMed
  57. ↵
    1. Wong ST,
    2. Trinh K,
    3. Hacker B,
    4. Chan GC,
    5. Lowe G,
    6. Gaggar A,
    7. Xia Z,
    8. Gold GH, and
    9. Storm DR
    (2000) Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice. Neuron 27:487–497.
    OpenUrlCrossRefPubMed
  58. ↵
    1. Woolsey TA and
    2. Van der Loos H
    (1970) The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex. The description of a cortical field composed of discrete cytoarchitectonic units. Brain Res 17:205–242.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Wu Z,
    2. Wong ST, and
    3. Storm DR
    (1993) Modification of the calcium and calmodulin sensitivity of the type I adenylyl cyclase by mutagenesis of its calmodulin binding domain. J Biol Chem 268:23766–23768.
    OpenUrlAbstract/FREE Full Text
  60. ↵
    1. Wu ZL,
    2. Thomas SA,
    3. Villacres EC,
    4. Xia Z,
    5. Simmons ML,
    6. Chavkin C,
    7. Palmiter RD, and
    8. Storm DR
    (1995) Altered behavior and long-term potentiation in type I adenylyl cyclase mutant mice. Proc Natl Acad Sci USA 92:220–224.
    OpenUrlAbstract/FREE Full Text
  61. ↵
    1. Xia Z,
    2. Choi EJ,
    3. Wang F, and
    4. Storm DR
    (1992) The type III calcium/calmodulin-sensitive adenylyl cyclase is not specific to olfactory sensory neurons. Neurosci Lett 144:169–173.
    OpenUrlCrossRefPubMed
  62. ↵
    1. Xia Z,
    2. Choi EJ,
    3. Wang F,
    4. Blazynski C, and
    5. Storm DR
    (1993) Type I calmodulin-sensitive adenylyl cyclase is neural specific. J Neurochem 60:305–311.
    OpenUrlCrossRefPubMed
  63. ↵
    1. Xia ZG,
    2. Refsdal CD,
    3. Merchant KM,
    4. Dorsa DM, and
    5. Storm DR
    (1991) Distribution of mRNA for the calmodulin-sensitive adenylate cyclase in rat brain: expression in areas associated with learning and memory. Neuron 6:431–443.
    OpenUrlCrossRefPubMed
  64. ↵
    1. Yeager RE,
    2. Heideman W,
    3. Rosenberg GB, and
    4. Storm DR
    (1985) Purification of the calmodulin-sensitive adenylate cyclase from bovine cerebral cortex. Biochem 24:3776–3783.
    OpenUrlCrossRefPubMed
  65. ↵
    1. Zalutsky RA and
    2. Nicoll RA
    (1990) Comparison of two forms of long-term potentiation in single hippocampal neurons. Science (Wash DC) 248:1619–1624.
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 63 (3)
Molecular Pharmacology
Vol. 63, Issue 3
1 Mar 2003
  • Table of Contents
  • About the Cover
  • Index by author
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Calmodulin-Regulated Adenylyl Cyclases: Cross-Talk and Plasticity in the Central Nervous System
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Review ArticleMINIREVIEW

Calmodulin-Regulated Adenylyl Cyclases: Cross-Talk and Plasticity in the Central Nervous System

Hongbing Wang and Daniel R. Storm
Molecular Pharmacology March 1, 2003, 63 (3) 463-468; DOI: https://doi.org/10.1124/mol.63.3.463

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Review ArticleMINIREVIEW

Calmodulin-Regulated Adenylyl Cyclases: Cross-Talk and Plasticity in the Central Nervous System

Hongbing Wang and Daniel R. Storm
Molecular Pharmacology March 1, 2003, 63 (3) 463-468; DOI: https://doi.org/10.1124/mol.63.3.463
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Update on Angiotensin II Subtype 2 Receptor Agonists
  • Neuronal Organoid Models in Drug Discovery
  • Arrestin-Dependent and -Independent Internalization of GPCRs
Show more Minireview

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics