Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuropeptide Y (NPY) receptors in the SK-N-MC human neuroblastoma cell line couple to mobilization of intracellular Ca2+ and inhibition of adenylylcyclase. Pretreatment of SK-N-MC cells with isoproterenol enhanced the NPY-stimulated Ca2+ mobilization, mainly by increasing the maximal response to NPY. The enhancement was time-(maximal after 24 h) and concentration-dependent (maximal at 10 microM isoproterenol), blocked by the beta-adrenergic antagonist propranolol, and mimicked by forskolin. Concomitant treatment with cycloheximide prevented the enhancing effect of isoproterenol, suggesting the involvement of protein synthesis. Isoproterenol treatment did not alter the number or affinity of 125I-labeled NPY binding sites, the amount of pertussis toxin substrates, or NPY-mediated inhibition of cAMP accumulation. Similarly, isoproterenol treatment had no effect on basal intracellular Ca2+ and on Ca2+ increases elicited by carbachol, caffeine, or ionomycin. We conclude that isoproterenol treatment can sensitize NPY receptor responsiveness in a way that is specific for Ca2+ mobilization mechanisms used by this hormone.
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PMID:NPY-stimulated Ca2+ mobilization in SK-N-MC cells is enhanced after isoproterenol treatment. 131 94

Neuropeptide Y (NPY) is one of the most abundant neuropeptides in the mammalian nervous system and exhibits a diverse range of important physiological activities, including effects on psychomotor activity, food intake, regulation of central endocrine secretion, and potent vasoactive effects on the cardiovascular system. Two major subtypes of NPY receptor (Y1 and Y2) have been defined by pharmacological criteria. We report here the molecular cloning of a cDNA sequence encoding a human NPY receptor and the corrected sequence for a rat homologue. Analysis of this sequence confirms that the receptor is a member of the G protein-coupled receptor superfamily. When expressed in Chinese hamster ovary (CHO) or human embryonic kidney (293) cells, the receptor exhibits the characteristic ligand specificity of a Y1 type of NPY receptor. In the 293 cell line, the receptor is coupled to a pertussis toxin-sensitive G protein that mediates the inhibition of cyclic AMP accumulation. In the CHO cell line, the receptor is coupled not to the inhibition of adenylate cyclase but rather to the elevation of intracellular calcium. These results demonstrate that second messenger coupling of the NPY-Y1 receptor is cell type specific, depending on the specific repertoire of G proteins and effector systems present in any cell type.
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PMID:Cloned human neuropeptide Y receptor couples to two different second messenger systems. 132 22

Immunocytochemistry and a radioimmunoassay were used to investigate the existence and distributions of various regulatory peptide immunoreactivities (ir) in human submandibular and parotid glands. Numerous nerve fibers containing vasoactive intestinal polypeptide (VIP) and peptide histidine methionine (PHM), or neuropeptide tyrosine (NPY) and C-flanking peptide of NPY (CPON)-ir were found in close proximity to acini, ducts and blood vessels. Only a few calcitonin gene-related peptide (CGRP)- and substance P (SP)-ir nerve fibers could be demonstrated and were mainly localized around blood vessels and ducts. Galanin and the recently discovered peptides helospectin and pituitary adenylate cyclase activating peptide were unable to be detected in the salivary glands studied. Preliminary quantitative investigations of four human submandibular glands using radioimmunoassay showed that VIP-ir had the highest concentration, followed by NPY-ir and CGRP-ir; SP-concentrations were below the detection limit. The possible physiological significance of these peptides for salivary secretion is discussed.
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PMID:[Peptidergic innervation of human salivary glands (parotid gland and submandibular gland)]. 133 45

Neuropeptide Y (NPY) inhibits cardiac adenylate cyclase activity by interacting with specific receptors coupled to a pertussis toxin-sensitive G protein. Structure-activity studies revealed that only C-terminal fragments can exhibit an NPY-like inhibitory effect on 125I-NPY binding and adenylate cyclase activity of rat cardiac ventricular membranes. Although NPY(17-36) inhibited 125I-NPY binding with high potency, it produced a biphasic effect on basal (GTP, 10 and 100 microM or guanosine 5'-gamma-O-(thio)triphosphate (GTP gamma S, 10 microM) adenylate cyclase activity. Low concentrations (less than 1 nM) of NPY(17-36) inhibited the adenylate cyclase activity whereas high concentrations (greater than 1 nM) reversed this action. GTP gamma S (100 microM) reversed the biphasic effect of NPY(17-36). NPY(17-36) exhibited only a stimulatory effect in the membranes from pertussis toxin-treated rats and an inhibitory effect with membranes from cholera toxin-treated rats. Low concentrations (less than 1 nM) of NPY(17-36) inhibited isoproterenol-stimulated adenylate cyclase activity whereas high doses (greater than 1 nM) reversed this activity. The cardiac NPY receptor antagonist, NPY(18-36) (1 microM), completely blocked the biphasic effect of NPY(17-36) on isoproterenol-stimulated activity. The inhibitory dose-response curve of NPY on isoproterenol-stimulated adenylate cyclase activity was shifted parallel to the right by NPY(17-36) (1 microM), suggesting that it is an antagonist of NPY at high concentrations. N-alpha-acetylated and C-terminally deamidated analogs of NPY(17-36) had no effect on the adenylate cyclase activity. [im-DNP-His26] NPY exhibited a more pronounced biphasic effect whereas N-alpha-myristoyl-NPY(17-36) elicited only a stimulatory effect. These investigations suggest that: 1) the inhibitory and stimulatory effects of NPY(17-36) are mediated by high affinity NPY receptors coupled to a pertussis toxin-sensitive G protein and a distinct population of low affinity receptors coupled to a cholera toxin-sensitive G protein, respectively; and 2) the stimulatory effect of NPY(17-36) is dissociable.
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PMID:Inhibitory and stimulatory effects of neuropeptide Y(17-36) on rat cardiac adenylate cyclase activity. Structure-function studies. 153 51

The existence, distribution and density of various neuropeptides in human submandibular and parotid glands were investigated using immunocytochemistry and radioimmunoassay. Numerous nerve fibers containing vasoactive intestinal polypeptide (VIP) and peptide histidine methionine (PHM), or neuropeptide Y (NPY) and C-flanking peptide of NPY (CPON) immunoreactivities (ir) were found in close association to acini, ducts and blood vessels. Only few calcitonin gene-related peptide (CGRP)- and substance P (SP)-ir nerve fibers could be demonstrated, mainly localized around blood vessels and ducts. Galanin and the newly discovered peptides helospectin and pituitary adenylate cyclase activating peptide (PACAP) could not be detected in human salivary glands.
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PMID:Neuropeptides in human salivary (submandibular and parotid) glands. 160 4

Neuropeptide Y (NPY) is a unique peptide with wide distribution in central and peripheral nervous systems. In the guinea pig, NPY-positive fibers are prominent in the myenteric plexus. To test whether NPY inhibits myenteric plexus acetylcholine (ACh) release and to define mechanisms, a purified preparation of myenteric plexus neurons was derived from the teniae coli of neonatal guinea pigs and maintained in primary culture. Incubation of cultured neurons labeled with [3H]ACh in the presence of NPY (10(-14)-10(-6) M) significantly inhibited basal ACh release (83 +/- 16 to 58 +/- 11% of control). NPY significantly inhibited ACh release stimulated by potassium (55 mM); by adenylate cyclase agonists forskolin (10(-6) M) and cholera toxin (10(-8) M); and by calcitonin gene-related peptide, cholecystokinin octapeptide, and vasoactive intestinal peptide (each 10(-8) M). In each instance, the inhibitory effects of NPY were reversed by preincubation with pertussis toxin. Reversal of inhibitory effects by pertussis toxin suggests that the actions of NPY are mediated via an inhibitory GTP-binding protein.
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PMID:Inhibition of acetylcholine release from guinea pig myenteric neurons by neuropeptide Y: GTP-binding protein mediation. 190 63

Neuropeptide Y is colocalized with norepinephrine in both central and peripheral noradrenergic neurons. In this study, we examined the regulatory mechanisms of neuropeptide Y on norepinephrine release in the medulla oblongata of rats. Neuropeptide Y inhibited the stimulation-evoked [3H]norepinephrine release in a dose-dependent manner in slices of medulla oblongata of Sprague-Dawley rats (1 Hz, S2/S1 ratio, control, 0.946 +/- 0.040 [+/- SEM], n = 6; neuropeptide Y 1 x 10(-8) M, 0.676 +/- 0.022, n = 6, p less than 0.05; neuropeptide Y 1 x 10(-7) M, 0.589 +/- 0.014, n = 6, p less than 0.05). Neuropeptide Y potentiated inhibition of [3H]norepinephrine release by the alpha 2-agonists UK 14,304 and clonidine. The blockade of alpha 2-adrenergic receptors by RX 781,094 diminished inhibitory effects of neuropeptide Y on norepinephrine release. Pretreatment of pertussis toxin (a toxin that interferes with the coupling of inhibitory receptors to adenylate cyclase) attenuated the suppression of norepinephrine release by neuropeptide Y. In spontaneously hypertensive rats, the inhibitory effect of UK 14,304 and neuropeptide Y on norepinephrine release from the medulla oblongata was significantly less than in age-matched Wistar-Kyoto rats. These results show that neuropeptide Y inhibits norepinephrine release partially mediated by alpha 2-adrenergic receptors and the pertussis toxin-sensitive guanosine triphosphate-binding proteins in rat medulla oblongata. Furthermore, less suppression of norepinephrine release by UK 14,304 and neuropeptide Y in spontaneously hypertensive rats suggests that alpha 2-adrenergic receptors and neuropeptide Y might be involved in the regulation of central sympathetic tone in hypertension.
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PMID:Norepinephrine release and neuropeptide Y in medulla oblongata of spontaneously hypertensive rats. 197 38

Neuropeptide Y (NPY) binding sites in rat cardiac ventricular membranes have been characterized in detail. 125I-NPY bound to the membranes with high affinity. Binding was saturable, reversible and specific, and depended on time, pH and temperature. Analysis of the binding data obtained under optimal conditions, 2 hr, 18 degrees C and at pH 7.5, revealed the presence of low and high affinity binding sites. The high affinity binding sites had an apparent dissociation constant (Kd) of 0.38 nM and a binding capacity (Bmax) of 7.13 fmol/mg protein. The apparent Kd and Bmax for low affinity binding sites were 22.34 nM and 261.25 fmol/mg protein, respectively. Peptides unrelated to NPY did not compete with 125I-NPY for the binding sites even at 1 microM concentrations, whereas homologous peptides, peptide YY (PYY) and pancreatic polypeptide (PP), and NPY(13-36) inhibited 125I-NPY binding but with lower potency compared to NPY. 125I-NPY binding was sensitive to the nonhydrolyzable GTP analog, Gpp(NH)p, suggesting that the NPY receptor is coupled to the adenylate cyclase system. The ventricular membrane receptor characterized in this study may play an important role in mediating the physiological effects of NPY in the heart.
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PMID:Characterization of neuropeptide Y binding sites in rat cardiac ventricular membranes. 216 78

Neuropeptide Y (NPY), a hexatriacontapeptide amide, is present in high concentrations in the mammalian heart. Specific receptors of NPY in rat cardiac ventricular membranes have been characterized recently in our laboratory. Structure-activity studies with selected partial sequences of NPY revealed that NPY(18-36) inhibited the binding of 125I-NPY to rat cardiac ventricular membranes but had no effect on the cardiac adenylate cyclase activity. NPY, as previously reported, inhibited the cardiac adenylate cyclase activity. These observations suggested that NPY (18-36) may be an antagonist of NPY in cardiac membranes. Consistent with this observation, the presence of NPY (18-36) (1 microM) shifted the inhibitory adenylate cyclase activity dose-response curve of NPY to the right in a parallel fashion. Furthermore, NPY(18-36) (1 microM) completely abolished the effect of NPY (10 nM) that alone caused 80% of the maximum inhibition of adenylate cyclase activity. These findings confirm that NPY(18-36) is a competitive antagonist of NPY in rat cardiac ventricular membranes. NPY cardiac receptor antagonist, NPY(18-36), or analogs based on this sequence may have potential clinical application, since NPY has been implicated in the pathophysiology of congestive heart failure.
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PMID:Neuropeptide Y (18-36) is a competitive antagonist of neuropeptide Y in rat cardiac ventricular membranes. 216 90

Neuropeptide Y (NPY) is released from an extensive network of postganglionic sympathetic perivascular neurons. NPY has been shown to affect vascular tone postsynaptically by 1) directly stimulating contraction; 2) inhibiting vasorelaxation; and 3) potentiating contraction elicited by exogenous vasoconstrictors. The molecular mechanisms mediating these effects of NPY are undefined. Therefore, we examined the possibility that NPY could stimulate smooth muscle contraction through myosin light chain phosphorylation in cultured porcine aortic smooth muscle cells. NPY (100 nM) caused a rapid, transient increase in myosin light chain (MLC) phosphorylation, an important regulatory event in the initiation of smooth muscle contraction. NPY-stimulated MLC phosphorylation was prevented by preincubation of cells with pertussis toxin and was independent of extracellular Ca2+. In parallel studies, NPY alone had no detectable effect on cellular cAMP or cGMP content; however, NPY potently inhibited forskolin-stimulated cAMP accumulation (IC50 = 0.03 nM) through a pertussis toxin-sensitive pathway. NPY had no detectable effect on basal phosphoinositide hydrolysis or protein kinase C activation but enhanced angiotensin II-stimulated production of inositol phosphates and activation of protein kinase C. These results indicate that NPY-stimulated MLC phosphorylation can occur in the absence of detectable changes in cAMP content, cGMP content, inositol phosphate production, or protein kinase C activation; however, the interactions between NPY and other vasoactive agents may be mediated by the indirect effects of NPY on adenylate cyclase activity and phosphoinositide hydrolysis.
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PMID:Neuropeptide Y stimulation of myosin light chain phosphorylation in cultured aortic smooth muscle cells. 217 Apr 10


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