Adenylate cyclase systems
The detailed molecular configuration of the adenyl cyclase is not known cyclase is not known but Rodwell believes it has two separate parts:
a) Receptor site which is regulator submit that binds it to substrate to which it will interact.
b) A catalytic submit that catalyses the reaction which culminates in the cascade phenomenon.
The activation of adenyl cyclase with hormone has shown that the activation is time-dependent, and it has a lagphase. It ahs een demonstrated that coupling efficient of enzyme activation and occupation of receptor by hormone varies with time. The first hormone – receptor complex formed will activate the adenyl cyclase synthesis more deficiently than complexes formed later on. This phenomenon is observed at low hormonal concentration. At high hormonal concentrations, its rate of enzyme activation is lower than the rate of hormone binding – this presupposes an existence of a rate limiting step within the mechanism of enzyme activation. Thus it can be said that coupling efficiency which is the amount of cyclic AMP reproduced in excess over basal value per number of ligand receptor complexes formed is maximal at low receptor occupancy but decreases in a progressive fashion as a result of saturation of receptor sites.
It has been shown that the activation of adenylate cyclase system can be modified by glucocorticoids. Dexamethasone induces stimulation of adenylate cyclase but aldosterone was found to be less effective and corticosterone not effective at all. This has led to the postulation that corticosteroids are important substances for the complete effect of coupling aiding coupling efficiency.
It has been shown that a specific receptor on a cell membrane can interact with other components of the adenylate cyclase system in another cell.
Modern view on the activation of adenylcyclase system has been considerably influenced by the following findings:
a) Using monkey erythrocytes, stimulation of adenylate cyclase by β-adrenergic agonists causes simultaneous stimulation of a membrane bound specific GTPase.
b) Cholera toxin which normally activates adenylate cyclase usually causes an inhibition of this as opposed to stimulation by B-adrenergic agonists. This inhibition of hormone-stimulated GTPase is caued by the transfer of GTPase to GTP binding sites.
c) Jakob and his associates in 1978 showed that stable GTP analogues will cause inhibition of GTP degradation and at the same time cause an irreversible stimulation of the adenylate cyclase system.
This led Cassel and later Limbird to postulate a new system interaction in which membrane receptors at basal level does not interact with G-protein which is guanine nucleotide-sensitive and a regulatory submit of the adenyl cyclase system vide supra nor does it interact with the catalytic component C.
However, when an agonist fits into the receptor molecule for the membrane, it activates the release of guanine nucleotide phosphate (GDP) from the G-component which then binds to the receptor when GTP is introduced to the R-G complex, it occupies the vacant site for guanine nucleotide the receptor – agonist complex and binds to the catalytic component of the adenylate cyclase system. The adenylate cyclase system is now an active form which can then catalyze the formation of c.AMP GTPase is ubiquitously present in the cell membrane to inhibit the formation of excess GTP in the G-protein. This is precisely what cholera toxin does. The binding of GTP to R-G protein complex causes the dissociation of the adenyl cyclase system leading to an increasing population of used receptors that possess lesser affinity for agonists. The synthesis of cAMP continues until it is turned off.
The whole of the cascade phenomena which occurs as a result of synthesis of cAMP is caused by the activation of cAMP dependent protein kinase which then phosphorylates specific proteins or enzymes leading to either inhibition or excitation; this includes action on chromosomal histone ones and non-linstones leading to repression or activation of specific genes that control specific metabolic processes in the cell.
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Creator: Oluwole Ogunranti