Regulation of Adenylyl Cyclase by Protein Kinase A

Iwami, Gensho; Kawabe, Jun‐ichi; Ebina, Toshiaki; Cannon, Paul J.; Homcy, Charles J.; Ishikawa, Yoshihiro

doi:10.1074/jbc.270.21.12481

Cited by 190 publications

(134 citation statements)

References 21 publications

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“…This unique property of G z a complements our finding of specific interaction of G z a with AC type V and suggests a critical role for both components in PKC-mediated cross-talk between G i and G q coupled receptor systems. Besides regulation by stimulatory and inhibitory G a subunits, enzymatic activity of AC type V is also subject to complex feedback inhibition by low micromolar concentrations of Ca 2+ (Krupinski et al 1992) and phosphorylation by PKA (Iwami et al 1995). In contrast, phosphorylation of AC type V by PKC markedly stimulates enzymatic activity (Kawabe et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Identity of adenylyl cyclase isoform determines the G protein mediating chronic opioid‐induced adenylyl cyclase supersensitivity

Ammer¹,

Christ²

2002

Journal of Neurochemistry

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To determine the intracellular signal transduction pathway responsible for the development of tolerance/dependence, the ability of G z a to substitute for pertussis toxin (PTX)-sensitive G proteins in mediating adenylyl cyclase (AC) supersensitivity was examined in the presence of defined AC isoforms. In transiently l-opioid receptor (OR) transfected COS-7 cells (endogenous inhibitory G proteins: G i a2, G i a3 and G z a), neither acute (1 lmol/L) nor chronic morphine treatment (1 lmol/L; 18 h) influenced intracellular cAMP production. Coexpression of the l-OR together with AC type V and VI fully restored the ability of morphine to acutely inhibit cAMP generation. Chronic morphine treatment further resulted in the development of tolerance/dependence, as assessed by desensitization of the acute inhibitory opioid effect (tolerance) as well as the induction of AC supersensitivity after drug withdrawal (dependence). Specific direction of l-OR signalling via G z a by both PTX treatment and G z a over-expression had no effect on chronic morphine regulation of AC type V, but completely abolished the development of tolerance/dependence with AC type VI. Similar results were obtained in stably l-OR-expressing HEK293 cells transiently cotransfected with G z a and either AC type V or VI. Coprecipitation studies further verified that G z a specifically binds to AC type V but not type VI. Taken together, these results demonstrate that in principle each of the OR-activated G proteins per se is able to mediate AC supersensitivity. However, they also indicate that it is the molecular nature of AC isoform that selects and determines the OR-activated G protein mediating tolerance/dependence.

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Section: Discussionmentioning

confidence: 99%

Identity of adenylyl cyclase isoform determines the G protein mediating chronic opioid‐induced adenylyl cyclase supersensitivity

Ammer¹,

Christ²

2002

Journal of Neurochemistry

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“…The activity of two related subtypes of AC, V and VI, was shown to be inhibited after phosphorylation by PKA (31). Therefore, we determined which AC subtypes were expressed by GT1 cells by RT-PCR analysis.…”

Section: Results Camp Regulation Of Gnrh Secretionmentioning

confidence: 99%

Role of the cAMP signaling pathway in the regulation of gonadotropin-releasing hormone secretion in GT1 cells

Vitalis

Costantin

Tsai

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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We studied the signaling pathways coupling gonadotropin-releasing hormone (GnRH) secretion to elevations in cAMP levels in the GT1 GnRH-secreting neuronal cell line. We hypothesized that increased cAMP could be acting directly by means of cyclic nucleotide-gated (CNG) cation channels or indirectly by means of activation of cAMP-dependent protein kinase (PKA). We showed that GT1 cells express the three CNG subunits present in olfactory neurons (CNG2, -4.3, and -5) and exhibit functional cAMP-gated cation channels. Activation of PKA does not appear to be necessary for the stimulation of GnRH release by increased levels of cAMP. In fact, pharmacological inhibition of PKA activity caused an increase in the basal secretion of GnRH. Consistent with this observation activation PKA inhibited adenylyl cyclase activity, presumably by inhibiting adenylyl cyclase V expressed in the cells. Therefore, the stimulation of GnRH release by elevations in cAMP appears to be the result of depolarization of the neurons initiated by increased cation conductance by cAMP-gated cation channels. Activation of PKA may constitute a negative-feedback mechanisms for lowering cAMP levels. We hypothesize that these mechanisms could result in oscillations in cAMP levels, providing a biochemical basis for timing the pulsatile release of GnRH.G onadotropin-releasing hormone (GnRH) secretion is controlled by a variety of regulatory mechanisms intrinsic to individual neurons or networks of GnRH-secreting neurons and by extrinsic regulatory mechanisms regulated by neurotransmitters released by efferent inputs to GnRH neurons. The development of the highly differentiated GT1 GnRH-secreting neuronal cell lines has provided a model to study the signaling mechanisms involved in the complex regulation of GnRH secretion (1). The GT1 cell lines were established from a hypothalamic tumor induced by genetic targeting of the expression of the oncogene encoding simian virus 40 T antigen to GnRH neurons in a transgenic mouse. The cells are highly differentiated and express and process GnRH at high levels (1, 2). The pulsatile release of GnRH appears to be an intrinsic property of individual or networks of GnRH neurons, since cultures of the GT1 cells release GnRH with a pulse frequency identical to that seen in castrate rodents (3-5). In vivo numerous efferent inputs to GnRH neurons release neurotransmitters that stimulate GnRH secretion (6). Neurotransmitters stimulating GnRH release from GT1 cells include bradykinin, dopamine (DA), endothelin, glutamate, neuropeptide Y, and norepinephrine (NE) (7-12).The current study is focused on the role of the cAMP signaling pathway in the regulation of GnRH secretion from GT1 cells. GT1 cells express both D1-DA receptors (8) and ␤1-adrenergic receptors (12) which are positively coupled to adenylyl cyclase (AC). Treatment of GT1 cells with DA or NE increased intracellular cAMP levels and stimulated GnRH secretion in a dose-dependent fashion (8, 12). The GnRH-releasing effects of DA and NE were mimicked by pharmacologically...

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“…In particular, adenylyl cyclases type V and VI, the major isoforms present in the adult heart (59), can be phosphorylated and inhibited by PKA (46,60). In order to check this hypothesis, the effect of H89 on ISO-stimulated I CNG was assessed in the presence of IBMX.…”

Section: Discussionmentioning

confidence: 99%

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

Rochais

Vandecasteele

Lefebvre

et al. 2004

Journal of Biological Chemistry

131

141

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Intracardiac cAMP levels are modulated by hormones and neuromediators with specific effects on contractility and metabolism. To understand how the same second messenger conveys different information, mutants of the rat olfactory cyclic nucleotide-gated (CNG) channel ␣-subunit CNGA2, encoded into adenoviruses, were used to monitor cAMP in adult rat ventricular myocytes. CNGA2 was not found in native myocytes but was strongly expressed in infected cells. In whole cell patchclamp experiments, the forskolin analogue L-858051 (L-85) elicited a non-selective, Mg 2؉ -sensitive current observed only in infected cells, which was thus identified as the CNG current (I CNG ). The ␤-adrenergic agonist isoprenaline (ISO) also activated I CNG , although the maximal efficiency was Ϸ5 times lower than with L-85. However, ISO and L-85 exerted a similar maximal increase of the L-type Ca 2؉ current. The use of a CNGA2 mutant with a higher sensitivity for cAMP indicated that this difference is caused by the activation of a localized fraction of CNG channels by ISO. cAMP-dependent protein kinase (PKA) blockade with H89 or PKI, or phosphodiesterase (PDE) inhibition with IBMX, dramatically potentiated ISO-and L-85-stimulated I CNG . A similar potentiation of ␤-adrenergic stimulation occurred when PDE4 was blocked, whereas PDE3 inhibition had a smaller effect (by 2-fold). ISO and L-85 increased total PDE3 and PDE4 activities in cardiomyocytes, although this effect was insensitive to H89. However, in the presence of IBMX, H89 had no effect on ISO stimulation of I CNG . This study demonstrates that subsarcolemmal cAMP levels are dynamically regulated by a negative feedback involving PKA stimulation of subsarcolemmal cAMP-PDE.Recent evidence indicates that multimolecular signaling complexes between cell surface receptors and intracellular targets are essential for the speed and specificity of signal transduction events (1, 2, 3). However, how such modules maintain specificity when small diffusible molecules are generated during the signaling cascade is difficult to investigate. This question is particularly relevant for cAMP in the heart, where this cyclic nucleotide second messenger exerts diverse effects in response to a number of different neuromediators and hormones. For instance, the ␤-adrenergic agonist isoprenaline (ISO), 1 prostaglandin E 1 (PGE 1 ), and glucagon-like peptide 1 (GLP-1) elevate intracardiac cAMP levels with different effects on contractility; ISO augments the force of contraction, PGE 1 does not, and GLP-1 exerts a negative inotropic effect (4, 5). In order to explain these results, subcellular compartmentation of cAMP was proposed more than 20 years ago (6).Localized cAMP signals may be generated by the interplay between discrete production sites and restricted diffusion within the cytoplasm. In addition to specialized membrane structures that may circumvent cAMP spreading (6, 7), degradation of cAMP into 5Ј-AMP by cyclic nucleotide phosphodiesterases (PDEs) appears critical for the formation of dynamic microdomain...

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Regulation of Adenylyl Cyclase by Protein Kinase A

Cited by 190 publications

References 21 publications

Identity of adenylyl cyclase isoform determines the G protein mediating chronic opioid‐induced adenylyl cyclase supersensitivity

Identity of adenylyl cyclase isoform determines the G protein mediating chronic opioid‐induced adenylyl cyclase supersensitivity

Role of the cAMP signaling pathway in the regulation of gonadotropin-releasing hormone secretion in GT1 cells

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

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