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Coupling of Receptors to Adenylate Cyclases

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 58 / 1))

Overview

Hormone- and neurotransmitter-sensitive adenylate cyclases are information-transfer systems that are dependent for their activities on Mg and are stimulated synergistically by guanine nucleotides and agonists. Three separate membranebound entities are responsible for the transmembrane signalling: receptor (R), the catalytic moiety of adenylate cyclase bearing the site that converts ATP to cAMP (C), and a guanine nucleotide-binding regulatory component (N) that affects receptor and catalytic component behavior, is a GTPase that hydrolyzes GTP to GDP, and acts as the actual coupler or transducer of the information transfer.

Studies on the kinetics of cAMP formation by isolated membrane particles containing functionally active hormone- and nucleotide-responsive adenylate cyclase systems have revealed that the basic readout system, i.e. the nucleotide-affected adenylate cyclase or CN complex, constitutes a hysteritic enzyme where binding of guanine nucleotide proceeds rapidly but the ensuing activation is slow, and that occupied hormone receptors are anti-hysteretic conferring to the system the capacity to respond rapidly to stimulatory nucleotides.

Kinetic studies on hormone and neurotransmitter binding to receptors have revealed, on the other hand, that guanine nucleotides promote a decrease in the apparent KD of the receptor-agonist interaction, indicating that receptors can exist in both a low affinity and a high afinity state. The latter is seen under conditions where its anti-hysteretic action is not observed and the former appears concomitantly with its anti-hysteretic effect.

N components can be extracted from membranes with detergents and shown to interact with C in solution or with C and R after reinsertion into N-deficient membranes such as provided by the so-called cyc - variant of S 49 lymphoma cells. Reconstitution studies of R and C regulation in cyc - membranes showed that guanine nucleotides including GTP, GDP, and analogs such as GMP-P(NH)P and GTPγS, not only affect C through interaction with N, but also affect the high to low affinity state transition of receptors through interaction with N. However, while GTP and its analogs stimulate basal adenylate cyclase activity and GDP and its analogs either do not affect it or inhibit it, both GTP and GTP-like as well as GDP and GDP-like compounds promote equally the appearance of so-called “low affinity” states of receptors.

This chapter describes and contrasts various schools of thought on the role that guanine nucleotides and the regulatory component N may have in regulating R and C. We discuss whether it is the high affinity or the low affinity form of the receptor that is the active one responsible for N-mediated activation of C, whether R does or does not form part of the hormone-affected activated adenylate cyclase complex and if so whether one or two N components need to form part of it, and whether the role of hormone-occupied receptors may be merely one of “facilitating” the activation of C by N.

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Birnbaumer, L., Iyengar, R. (1982). Coupling of Receptors to Adenylate Cyclases. In: Nathanson, J.A., Kebabian, J.W. (eds) Cyclic Nucleotides. Handbook of Experimental Pharmacology, vol 58 / 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-68111-0_3

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