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)

In the guinea pig myometrium, muscarinic receptor activation leads to contraction and elicits two biochemical responses viz. an increased formation of inositol phosphates (via a guanine nucleotide regulatory protein, distinct from the stimulatory and inhibitory G proteins of the adenylate cyclase system and a decreased synthesis of cyclic AMP involving inhibitory G protein activation. We now describe two major differences in the effects of muscarinic agonists. First, the greater potency of carbachol in inhibiting cyclic AMP formation (EC50 = 8 nM) than in stimulating the accumulation of inositol phosphates and tension (EC50 = 15 and 2 microM, respectively). Second, carbachol, oxotremorine and pilocarpine were equally effective in eliciting cyclic AMP inhibition but the order of potency for inositol phosphate formation was carbachol greater than oxotremorine and pilocarpine was without effect. The partial agonists, pilocarpine and oxotremorine, inhibited carbachol-mediated inositol phosphate formation. Pirenzepine, selective for muscarinic M1 receptor subtype, displayed a low affinity for antagonizing cyclic AMP inhibition, inositol phosphate generation and tension due to carbachol (Ki = 286, 92 and 110 nM, respectively). AF-DX116 (11-[( 2-[(diethylamino)methyl]-1- piperidinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine- 6-one), selective for cardiac M2 receptors blocked cyclic AMP inhibition with high affinity (Ki = 1.14 nM) while it antagonized inositol phosphate formation with low affinity (Ki = 346 nM). Both high (Ki = 1 nM) and low (Ki = 100 nM) affinities were displayed by AF-DX116 in antagonizing contractions due to carbachol (24 and 76% inhibition, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological evidence for distinct muscarinic receptor subtypes coupled to the inhibition of adenylate cyclase and to the increased generation of inositol phosphates in the guinea pig myometrium. 215 62

In primary cultures of cerebellar granule cells, activation of muscarinic receptors stimulates both hydrolysis of phosphatidylinositol (PI) and inhibition of adenylate cyclase. The specificity of three muscarinic receptor antagonists, pirenzepine, methoctramine and (-)quinuclidinyl xanthene-9-carboxylate [(-)QNX], in blocking carbachol-stimulated hydrolysis of PI and inhibition of adenylate cyclase were determined. Pirenzepine was found to be nonspecific in blocking the carbachol-stimulated hydrolysis of PI and inhibition of adenylate cyclase, while methoctramine specifically antagonized carbachol-stimulated inhibition of adenylate cyclase with 600 times greater potency than carbachol-stimulated hydrolysis of PI. (-)Quinuclidinyl xanthene-9-carboxylate was approximately 20 times more potent in blocking the carbachol-stimulated hydrolysis of PI than inhibition of adenylate cyclase. Studies of the ability of these three antagonists to block the binding of [3H]quinuclidinyl benzilate [( 3H]QNB) to muscarinic sites on membranes from cerebellar granule cells, revealed that all three antagonists displayed binding characteristics, characteristic of two binding sites, possibly representing the two types of muscarinic receptors. However, the ratio of the affinities for each of the two binding sites was about ten for pirenzepine, 100 for methoctramine and 650 for (-)QNX. Thus, the specificity of these antagonists, in blocking the inhibition of adenylate cyclase and hydrolysis of PI did not correlate with their specificities obtained with the binding studies with [3H]QNB.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specificity of methoctramine in blocking muscarinic receptors which inhibit adenylate cyclase in cerebellar granule cells. 229 64

Pharmacological differences between muscarinic cholinergic receptors coupled to phosphoinositide turnover and those coupled to adenylate cyclase were studied. Stimulation of muscarinic receptors from SK-N-SH human neuroblastoma cells resulted in phosphoinositide hydrolysis, but not in inhibition of cAMP formation. As has been shown previously, stimulation of muscarinic receptors from NG108-15 neuroblastoma x glioma cells, on the other hand, resulted in inhibition of cAMP formation without any observable phosphoinositide hydrolysis. These two cell lines provide a useful model system in which to study differential coupling of muscarinic cholinergic receptors. Inhibition of [3H]N-methyl scopolamine [( 3H]NMS) binding and inhibition of carbachol-stimulated function by the antagonists pirenzepine, AF-DX 116, and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) were studied in this system. Pirenzepine inhibited [3H]NMS binding in both cell lines with low affinity (Ki of 130 and 160 nM in NG108-15 and SK-N-SH cells respectively), indicating that both cell lines express M2 receptors. None of the three antagonists studied exhibited any clear selectivity for the receptors in one cell line over those of the other. In contrast, several agonists including acetylcholine, bethanechol and carbachol exhibited pronounced selectivity. These agonists inhibited [3H]NMS binding to membranes from SK-N-SH cells with IC50 values that were 17-, 3- and 38-fold higher, respectively, than those of NG108-15 cells. This selectivity was still observed when whole cells rather than membranes were studied. These findings indicate that pharmacological differences between receptors coupled to phosphoinositide turnover and those coupled to cAMP inhibition can be detected with certain agonists, but not with the antagonists pirenzepine, AF-DX 116 or 4-DAMP.
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PMID:Pharmacological differences between muscarinic receptors coupled to phosphoinositide turnover and those coupled to adenylate cyclase inhibition. 247 34

The coupling of the muscarinic receptor to the inhibition of the adenylate cyclase system was studied in adult rat cortical tissue dissociated by teasing tissue minces through finely meshed Nitex filters. The intracellular ATP stores in the final preparation were metabolically prelabeled with [3H]adenine and the [3H]cAMP formed in the tissue was isolated by ion exchange chromatography. Forskolin (3-30 microM) elevated [3H]cAMP levels 5- to 9-fold over basal in the preparation, with maximum stimulation achieved by 10-15 min. In the dissociated cortex, carbachol inhibited forskolin-elevated [3H]cAMP levels with an EC50 value of 1.4 microM; maximal inhibition was in the range of 20-30%. Atropine completely blocked the response (Ki = 1.8 nM), which showed that carbachol stimulates a muscarinic receptor to inhibit [3H]cAMP levels in this preparation. Pirenzepine, an M1-selective antagonist, blocked the response to carbachol with low potency (Ki = 467 nM), which indicated that an M2 muscarinic receptor subtype mediates [3H]cAMP inhibition in the cortex. The response to 10 microM carbachol was not affected by 10 mM EGTA, 50 microM D-tubocurarine, or 100 nM tetrodotoxin; thus, activation of nicotinic receptors or a neuronal release process was not involved. [3H]cAMP reduction in response to muscarinic stimulation was also observed in dissociated tissue prepared from other brain regions. A robust response was encountered in striatal preparations (maximal inhibition 40%), while hippocampal responses were smaller and less reproducible than in the cortex. The striatal response was shown to be pharmacologically similar to the cortical response.
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PMID:Muscarinic M2 receptor-mediated cyclic AMP reduction in mechanically dissociated rat cortex. 285 Aug 35

The muscarinic agonist oxotremorine produced a linear dose-dependent increase in membrane fluidity of intact and viable human lymphocytes in vitro. This effect proved to be receptor-mediated because preincubation with 10(-5)M atropine shifted the dose-response curve one order of magnitude rightward. Pirenzepine preincubation did not affect membrane fluidity variation. A cGMP increase was also found after oxotremorine treatment. The results are discussed in terms of possible modulation of guanyl cyclase and adenyl cyclase through membrane fluidity variations.
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PMID:Intact human lymphocyte membranes respond to muscarinic receptor stimulation by oxotremorine with marked changes in microviscosity and an increase in cyclic GMP. 299 66

1. The affinities of 10 selective muscarinic receptor antagonists against [3H]-quinuclidinyl benzilate (QNB) binding were determined to characterize the muscarinic receptors present in guinea-pig gallbladder smooth muscle. The highest correlation was obtained for the comparison between the pKi values for the gallbladder smooth muscle and M2 sites. Pirenzepine revealed two binding sites with affinities indicating the presence of muscarinic M2 receptors in abundance and a minor population of an additional site(s). 2. Carbachol produced gallbladder contractions, stimulated phosphoinositide (PI) hydrolysis and inhibited cAMP formation concentration-dependently with pD2 values of 6.12 +/- 0.11, 5.18 +/- 0.33 and 7.19 +/- 0.15, respectively. 3. Pirenzepine, 4-DAMP, HHSiD, pF-HHSiD, AF-DX 116, methoctramine, AQ-RA 741, guanylpirenzepine and AF-DX 384 showed competitive antagonism against carbachol-induced gallbladder contractions. There was no correlation between the pA2 values for the gallbladder and pKi values for the M2 sites, whereas significant correlations were found for the M1, M3 and M4 sites, the best correlation being between the pA2 values for the gallbladder and M4 subtypes. 4. Finally, the presence of both m2 and m4 receptor proteins were demonstrated by Western blot analysis. It is concluded that guinea-pig gallbladder smooth muscle has both muscarinic M2 and M4 receptors, which are coupled to adenylate cyclase inhibition and PI hydrolysis. 5. Although it seems likely that M2 receptors do not play a primary role in carbachol-induced guinea-pig gallbladder contraction, the characterization of the muscarinic subtypes which mediate these contractile responses needs further evidence.
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PMID:Evidence for the presence of muscarinic M2 and M4 receptors in guinea-pig gallbladder smooth muscle. 978 89

This study characterizes the muscarinic cholinergic receptors associated with the inhibition of adenylate cyclase on N18TG2 neuroblastoma cell membranes. Agonists could be divided into two classes: oxotremorine, acetylcholine, carbachol and arecoline exerted the most efficacious and potent inhibition, while McN-A343, bethanechol and AHR-602 were partial agonists. Both quinuclidinyl benzilate and atropine maximally antagonized the inhibitory effect of McN-A343, carbachol and oxotremorine. Pirenzepine was almost as potent as atropine in reversing the inhibitory effect of McN-A343, but was 300 times less potent than atropine or quinuclidinyl benzilate in antagonizing the effects of either carbachol or oxotremorine. Gallamine was ineffective as an antagonist at concentrations up to 1 mM. These results suggest that the receptors that modulate this inhibition are of the M(2) type, since they were activated by carbachol, acetylcholine and oxotremorine, but much less by McN-A343 and AHR-602 (both M(1) selective agonists). The full agonists were blocked by atropine and quinuclidinyl benzilate but not by low concentrations of pirenzepine (M(1) selective antagonist).
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PMID:Muscarinic pharmacology of the inhibition of adenylate cyclase in N18TG2 neuroblastoma cells. 2050 Nov 73