Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the glucagon/secretin peptide family, has been recently proposed to be the ancestral GH-releasing factor. Using grass carp as a model for bony fish, we examined the mechanisms for PACAP regulation of GH synthesis and secretion at the pituitary level. Nerve fibers with PACAP immunoreactivity were identified in the grass carp pituitary overlapping with the distribution of somatotrophs. At the somatotroph level, PACAP was shown to induce cAMP synthesis and Ca(2+) entry through voltage-sensitive Ca(2+) channels (VSCC). In carp pituitary cells, PACAP but not vasoactive intestinal polypeptide increased GH release, GH content, total GH production, and steady-state GH mRNA levels. PACAP also enhanced GH mRNA stability, GH promoter activity, and nuclear expression of GH primary transcripts. Increasing cAMP levels, induction of Ca(2+) entry, and activation of VSCC were all effective in elevating GH secretion and GH mRNA levels. PACAP-induced GH secretion and GH mRNA expression, however, were abolished by inhibiting adenylate cyclase and protein kinase A, removing extracellular Ca(2+) or VSCC blockade, or inactivating calmodulin (CaM)-dependent protein kinase II (CaM kinase II). Similar sensitivity to VSCC and CaM kinase II blockade was also observed by activating cAMP production as a trigger for GH release and GH gene expression. These results suggest that PACAP stimulates GH synthesis and secretion in grass carp pituitary cells through PAC(1) receptors. These stimulatory actions probably are mediated by the adenylate cyclase/cAMP/protein kinase A pathway coupled to Ca(2+) entry via VSCC and subsequent activation of CaM/CaM kinase II cascades.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) as a growth hormone (GH)-releasing factor in grass carp. I. Functional coupling of cyclic adenosine 3',5'-monophosphate and Ca2+/calmodulin-dependent signaling pathways in PACAP-induced GH secretion and GH gene expression in grass carp pituitary cells. 1612 57

Thalamic nuclei can generate intrathalamic rhythms similar to those observed at various arousal levels and pathophysiological conditions such as absence epilepsy. These rhythmic activities can be altered by a variety of neuromodulators that arise from brain stem regions as well as those that are intrinsic to the thalamic circuitry. Vasoactive intestinal peptide (VIP) is a neuropeptide localized within the thalamus and strongly attenuates intrathalamic rhythms via an unidentified receptor subtype. We have used transgenic mice lacking a specific VIP receptor, VPAC(2), to identify its role in VIP-mediated actions in the thalamus. VIP strongly attenuated both the slow, 2-4 Hz and spindle-like 5-8 Hz rhythmic activities in slices from wild-type mice (VPAC(2)(+/+)) but not in slices from VPAC(2) receptor knock-out mice (VPAC(2)(-/-)), which suggests a major role of VPAC(2) receptors in the antioscillatory actions of VIP. Intracellular recordings revealed that VIP depolarized all relay neurons tested from VPAC(2)(+/+) mice. In VPAC(2)(-/-) mice, however, VIP produced no membrane depolarization in 80% of neurons tested. In relay neurons from VPAC(2)+/+ mice, VIP enhanced the hyperpolarization-activated mixed cation current, I(h), via cyclic AMP activity, but VIP did not alter I(h) in VPAC(2)-/- mice. In VPAC(2)-/- mice, pituitary adenylate cyclase activating-polypeptide (PACAP) depolarized the majority of relay neurons via I(h) enhancement presumably via PAC(1) receptor activation. Our findings suggest that VIP-mediated actions are predominantly mediated by VPAC(2) receptors, but PAC(1) receptors may play a minor role. The excitatory actions of VIP and PACAP suggest these peptides may not only regulate intrathalamic rhythmic activities, but also may influence information transfer through thalamocortical circuits.
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PMID:Excitatory actions of vasoactive intestinal peptide on mouse thalamocortical neurons are mediated by VPAC2 receptors. 1664 77

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are the main endogenous ligands of a class of G protein-coupled receptors (Rs). Three subtypes of PACAP/VIP Rs have been identified and named PAC(1)-Rs, VPAC(1)-Rs, and VPAC(2)-Rs. The PAC(1)-R almost exclusively binds PACAP, while the other two subtypes bind with about equal efficiency VIP and PACAP. VIP, PACAP, and their receptors are widely distributed in the body tissues, including the adrenal gland. VIP and PACAP are synthesized in adrenomedullary chromaffin cells, and are released in the adrenal cortex and medulla by VIPergic and PACAPergic nerve fibers. PAC(1)-Rs are almost exclusively present in the adrenal medulla, while VPAC(1)-Rs and VPAC(2)-Rs are expressed in both the adrenal cortex and medulla. Evidence indicates that VIP and PACAP, acting via VPAC(1)-Rs and VPAC(2)-Rs coupled to adenylate cyclase (AC)- and phospholipase C (PLC)-dependent cascades, stimulate aldosterone secretion from zona glomerulosa (ZG) cells. There is also proof that they can also enhance aldosterone secretion indirectly, by eliciting the release from medullary chromaffin cells of catecholamines and adrenocorticotropic hormone (ACTH), which in turn may act on the cortical cells in a paracrine manner. The involvement of VIP and PACAP in the regulation of glucocorticoid secretion from inner adrenocortical cells is doubtful and surely of minor relevance. VIP and PACAP stimulate the synthesis and release of adrenomedullary catecholamines, and all three subtypes of PACAP/VIP Rs mediate this effect, PAC(1)-Rs being coupled to AC, VPAC(1)-Rs to both AC and PLC, and VPAC(2)-Rs only to PLC. A privotal role in the catecholamine secretagogue action of VIP and PACAP is played by Ca(2+). VIP and PACAP may also modulate the growth of the adrenal cortex and medulla. The concentrations attained by VIP and PACAP in the blood rule out the possibility that they act as true circulating hormones. Conversely, their adrenal content is consistent with a local autocrine-paracrine mechanism of action.
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PMID:Endogenous ligands of PACAP/VIP receptors in the autocrine-paracrine regulation of the adrenal gland. 1669 81

Three receptors for VIP and pituitary adenylate cyclase-activating peptide (PACAP) have been cloned and characterized: PAC(1), with high affinity for PACAP, and VPAC(1) and VPAC(2) with equally high affinity for VIP and PACAP. The existence of a VIP-specific receptor (VIP(s)) in guinea pig (GP) teniae coli smooth muscle was previously surmised on the basis of functional studies, and its existence was confirmed by cloning of a partial NH(2)-terminal sequence. Here we report the cloning of the full-length cDNAs of two receptors, a VPAC(2) receptor from GP gastric smooth muscle and VIP(s) from GP teniae coli smooth muscle. The cDNA sequence of the VIP(s) encodes a 437-amino acid protein (M(r) 49,560) that possesses 87% similarity to VPAC(2) receptors in rat and mouse and differs from the VPAC(2) receptor in GP gastric smooth muscle by only two amino-acid residues, F(40)F(41) in lieu of L(40)L(41). In COS-1 cells transfected with the GP teniae coli smooth muscle receptor, only VIP bound with high affinity (IC(50) 1.4 nM) and stimulated cAMP formation with high potency (EC(50) 1 nM). In contrast, in COS-1 cells transfected with the GP gastric smooth muscle receptor, both VIP and PACAP bound with equally high affinity (IC(50) 2.3 nM) and stimulated cAMP with equally high potency (EC(50) 1.5 nM). We conclude that the receptor cloned from GP teniae coli smooth muscle is a VIP(s) distinct from VPAC(1) and VPAC(2) receptors. The ligand specificity in this species is determined by a pair of adjacent phenylalanine residues (L(40)L(41)) in the NH(2)-terminal ligand-binding domain.
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PMID:Molecular cloning and functional expression of a VIP-specific receptor. 1695 56

Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a (1;11) (q42.1;q14.3) translocation that segregates with major psychiatric disorders in a Scottish family. To investigate how DISC1 confers susceptibility to psychiatric disorders, we previously identified fasciculation and elongation protein zeta-1 and Kendrin as DISC1-interacting molecules in a yeast two-hybrid screen of a human brain complementary DNA library. Here, we have further identified a novel DISC1-interacting protein, termed DISC1-Binding Zinc-finger protein (DBZ), which has a predicted C(2)H(2)-type zinc-finger motif and coiled-coil domains. DBZ was co-immunoprecipitated with DISC1 in lysates of PC12 cells and rat brain tissue. The domain of DISC1 interacting with DBZ was close to the translocation breakpoint in the DISC1 gene. DBZ messenger RNA (mRNA) was expressed in human brains, but not in peripheral tissues. In situ hybridization revealed high expression of DBZ mRNA in the hippocampus, olfactory tubercle, cerebral cortex and striatum in rats. Because this pattern of localization was similar to that of the pituitary adenylate cyclase (PAC(1)) receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), which has recently been implicated in neuropsychological functions, we examined whether DISC1/DBZ interaction was involved in the PACAP signaling pathway. PACAP upregulated DISC1 expression and markedly reduced the association between DISC1 and DBZ in PC12 cells. A DISC1-binding domain of DBZ reduced the neurite length in PC12 cells after PACAP stimulation and in primary cultured hippocampal neurons. The present results provide some new molecular insights into the mechanisms of neuronal development and neuropsychiatric disorders.
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PMID:A novel DISC1-interacting partner DISC1-Binding Zinc-finger protein: implication in the modulation of DISC1-dependent neurite outgrowth. 1738 5

Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G protein)-coupled receptors (GPCR). Examples of islet GPCR are GPR40 and GPR119, which are GPCR with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors acetylcholine (ACh; M(3) muscarinic receptors) and noradrenaline (beta(2)- and alpha(2)-adrenoceptors) and for the neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP; PAC(1) and VPAC(2) receptors), cholecystokinin (CCK(A) receptors) and neuropeptide Y (NPY Y1 receptors). Other islet GPCR are the cannabinoid receptor (CB(1) receptors), the vasopressin receptors (V1(B) receptors) and the purinergic receptors (P(2Y) receptors). The islet GPCR couple mainly to adenylate cyclase and to phospholipase C (PLC). Since important pharmacological strategies for treatment of type 2 diabetes are stimulation of insulin secretion and inhibition of glucagon secretion, islet GPCR are potential drug targets. This review summarizes knowledge on islet GPCR.
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PMID:G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes. 1790 Jul

Vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase activating polypeptides (PACAPs) share 68% identity at the amino acid level and belong to the secretin peptide family. Following the initial discovery of VIP almost four decades ago a substantial amount of knowledge has been presented describing the mechanisms of action, distribution and pleiotropic functions of these related peptides. It is now known that the physiological actions of these widely distributed peptides are produced through activation of three common G-protein coupled receptors (VPAC(1), VPAC(2) and PAC(1)R) which preferentially stimulate adenylate cyclase and increase intracellular cAMP, although stimulation of other intracellular messengers, including calcium and phospholipase D, has been reported. Using a range of in vitro and in vivo approaches, including cell-based functional assays, transgenic animals and rodent models of disease, VPAC/PAC receptor activation has been associated with numerous physiological processes (e.g. control of circadian rhythms) and clinical conditions (e.g. pulmonary hypertension), which underlies on-going research efforts and makes these peptides and their cognate receptors attractive targets for the pharmaceutical industry. However, despite the considerable interest in VPAC/PAC receptors and the processes which they mediate, there is still a paucity of selective and available, non-peptide ligands, which has hindered further advances in this field both at the basic research and clinical level. This review summarises the current knowledge of VIP/PACAP and the VPAC/PAC receptors with regard to their distribution, pharmacology, signalling pathways, splice variants and finally, the utility of animal models in exploring their physiological roles.
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PMID:VPAC and PAC receptors: From ligands to function. 1910 92

In the goldfish pituitary, nerve fibers containing pituitary adenylate cyclase-activating polypeptide (PACAP) are located in close proximity to somatolactin (SL)-producing cells, and PACAP enhances SL release from cultured pituitary cells. However, there is little information about the mechanism of PACAP-induced SL release. In order to elucidate this issue, we used the cell immunoblot method. Treatment with PACAP at 10(-8) and 10(-7)M, but not with vasoactive intestinal polypeptide (VIP) at the same concentrations, increased the immunoblot area for SL-like immunoreactivity from dispersed pituitary cells, and PACAP-induced SL release was blocked by treatment with the PACAP selective receptor (PAC(1)R) antagonist, PACAP(6-38), at 10(-6)M, but not with the PACAP/VIP receptor antagonist, VIP(6-28). PACAP-induced SL release was also attenuated by treatment with the calmodulin inhibitor, calmidazolium at 10(-6)M. This led us to explore the signal transduction mechanism up to SL release, and we examined whether PACAP-induced SL release is mediated by the adenylate cyclase (AC)/cAMP/protein kinase A (PKA)- or the phospholipase C (PLC)/inositol 1,4,5-trisphosphate (IP(3))/protein kinase C (PKC)-signaling pathway. PACAP-induced SL release was attenuated by treatment with the AC inhibitor, MDL-12330A, at 10(-5)M or with the PKA inhibitor, H-89, at 10(-5)M. PACAP-induced SL release was suppressed by treatment with the PLC inhibitor, U-73122, at 3 x 10(-6)M or with the PKC inhibitor, GF109203X, at 10(-6)M. These results suggest that PACAP can potentially function as a hypophysiotropic factor mediating SL release via the PAC(1)R and subsequently through perhaps the AC/cAMP/PKA- and the PLC/IP(3)/PKC-signaling pathways in goldfish pituitary cells.
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PMID:Pituitary adenylate cyclase-activating polypeptide induces somatolactin release from cultured goldfish pituitary cells. 1954 Apr 24

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) and their class II G protein-coupled receptors VPAC(1), VPAC(2), and PAC(1) play important roles in human physiology. No small molecule modulator has ever been reported for the VIP/PACAP receptors, and there is a lack of specific VPAC(2) antagonists. Via high-throughput screening of 1.67 million compounds, we discovered a single small molecule antagonist of human VPAC(2), compound 1. Compound 1 inhibits VPAC(2)-mediated cAMP accumulation with an IC(50) of 3.8 microM and the ligand-activated beta-arrestin2 binding with an IC(50) of 2.3 microM. Compound 1 acts noncompetitively in Schild analysis. It is a specific VPAC(2) antagonist with no detectable agonist or antagonist activities on VPAC(1) or PAC(1). Compound 2, a close structural analog of compound 1, was also found to be weakly active. To our surprise, compound 1 is completely inactive on the closely related mouse VPAC(2). Chimera experiments indicate that compounds 1 and 2 bind to the seven transmembrane (7TM) region of the receptor as opposed to the N-terminal extracellular domain, where the natural ligand binds. Compound 1, being the first small molecular antagonist that is specific for VPAC(2), and the only VPAC(2) antagonist molecule known to date that allosterically interacts with the 7TM region, will be a valuable tool in further study of VPAC(2) and related receptors. This study also highlights the opportunities and challenges facing small molecule drug discovery for class II peptide G protein-coupled receptors.
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PMID:Identification and characterization of a small molecule antagonist of human VPAC(2) receptor. 1985 90

Neuropeptides collaborate with conventional neurotransmitters to regulate synaptic output. Pituitary adenylate cyclase-activating polypeptide (PACAP) co-localizes with acetylcholine in presynaptic nerve terminals, is released by stimulation, and enhances nicotinic acetylcholine receptor- (nAChR-) mediated responses. Such findings implicate PACAP in modulating nicotinic neurotransmission, but relevant synaptic mechanisms have not been explored. We show here that PACAP acts via selective high-affinity G-protein coupled receptors (PAC(1)Rs) to enhance transmission at nicotinic synapses on parasympathetic ciliary ganglion (CG) neurons by rapidly and persistently increasing the frequency and amplitude of spontaneous, impulse-dependent nicotinic excitatory postsynaptic currents (sEPSCs). Of the canonical adenylate cyclase (AC) and phospholipase-C (PLC) transduction cascades stimulated by PACAP/PAC(1)R signaling, only AC-generated signals are critical for synaptic modulation since the increases in sEPSC frequency and amplitude were mimicked by 8-Bromo-cAMP, blocked by inhibiting AC or cAMP-dependent protein kinase (PKA), and unaffected by inhibiting PLC. Despite its ability to increase agonist-induced nAChR currents, PACAP failed to influence nAChR-mediated impulse-independent miniature EPSC amplitudes (quantal size). Instead, evoked transmission assays reveal that PACAP/PAC(1)R signaling increased quantal content, indicating that it modulates synaptic function by increasing vesicular ACh release from presynaptic terminals. Lastly, signals generated by the retrograde messenger, nitric oxide- (NO-) are critical for the synaptic modulation since the PACAP-induced increases in spontaneous EPSC frequency, amplitude and quantal content were mimicked by NO donor and absent after inhibiting NO synthase (NOS). These results indicate that PACAP/PAC(1)R activation recruits AC-dependent signaling that stimulates NOS to increase NO production and control presynaptic transmitter output at neuronal nicotinic synapses.
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PMID:PACAP/PAC1R signaling modulates acetylcholine release at neuronal nicotinic synapses. 1995 33


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