Catecholamine-specific desensitization of adenylate cyclase. Evidence for a multistep process.
Journal of Biological ChemistryPublished 1 August 1980Open access
Y F Su, T K Harden, John P. Perkins
Citations338
SJR quartileQ1
SJR score1.71
SNIP1.00
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Abstract
I-HYP, '251-hydroxybenzylpindolol; Gpp(NH)p, guanyl-5'-yl imido
Keywords
NeuroscienceBiochemistry, Genetics and Molecular Biology
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It is proposed that continuous GTP hydrolysis at the regulatory guanyl nucleotide site is an essential turn-off mechanism, terminating activation of the adenylate cyclase.
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The properties of ligand binding to the beta-adrenergic receptor have been studied using a computer modeling technique to analyze data obtained by indirect binding methods and the ability of an agonist to activate adenylate cyclase correlates closely with the amount of high affinity state formed in the presence of the agonist.
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The findings indicate that the inactive adenylate cyclase possesses tightly bound GDP, produced by the hydrolysis of GTP at the regulatory site, which the hormone stimulates by inducing an "opening" of the guanyl nucleotide site.
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The data suggest that stimulation of the beta-adrenergic receptor causes a rapid decrease in the number of available receptors and in hormone-sensitive adenylate cyclase activity; conversely, lack of stimulation causes an increase in these parameters.
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The S49 mouse lymphoma cell line is used to study the increase and subsequent decrease in cyclic AMP levels (termed refractoriness) following incubation of cells with isoproterenol, and suggests that adenylate cyclase may exert regulatory controls on beta-adrenergic receptors in addition to generation of cyclicAMP.
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The frog erythrocyte membrane provides an excellent model system for the study of beta-adrenergic receptor-adenylate cyclase interactions since it possesses an adenylate Cyclase enzyme which is very responsive to catecholamines.
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It is concluded that the loss of beta-adrenergic receptors is an event that occurs as a result of the initial uncoupling of the beta-receptor-linked adenylate cyclase.
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Iodohydroxybenzylpindolol (IHYP) proved to be the most useful ligand, and the properties of the binding of IHYP to proteins derived from rat ventricular muscle have been characterized.
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The results suggest that just as short-term regulation of cyclic AMP levels occurs via changes in the rates of synthesis or degradation, long-term alterations of the system may also involve either the adenylate cyclase or the phosphodiesterase.
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Agonist binding studies may now be used to assess more completely the desensitized state of beta-adrenergic receptors in systems in which marked desensitization of beta-adrenergic responses is associated with little or no reduction in antagonist binding.
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Findings are consistent with a model of beta-adrenergic receptor desensitization in which desensitized receptors arise from receptors in the high affinity state, with chronic occupancy by agonist, which appears to result in selective loss or inactivation of these high affinity agonist binding sites.
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These studies of binding to beta adrenergic receptors of intact cultured cells using either [125I]IHYP or [3H]DHA offer a useful tool that should complement and extend studies of receptors on plasma membranes isolated from such cells.
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Comparison of the rates of cAMP accumulation by and disappearance from intact cells provided evidence that cells treated with norepinephrine hydrolyzed cAMP more rapidly than did naive cells.
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The ability to decrease receptor number maximally was directly correlated with maximum ability to stimulate adenylate cyclase (intrinsic activity) and the specificity of this process in membranes was that of a beta adrenergic receptor-mediated effect.
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It can be demonstrated that cells maintained in culture for prolonged periods (months to years) may lose responsiveness to specific agonists while responsiveness to other agonists remains unchanges or actually increases.
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