PLEASE READ AND ANSWER CAREFULLY!! In studies trying to understand the regulatio

Question

PLEASE READ AND ANSWER CAREFULLY!!

In studies trying to understand the regulation of hormone-sensitive adenylate cyclase, it was discovered that non-hydrolyzable GTP analogs and cholera toxin (that inhibits the GTPase activity of Gs) were able to activate the enzyme in a sustained (irreversible) profile, therefore indicating that GTP hydrolysis represents a deactivation (turn-off) regulatory step.

a) Will these analogs or toxin have any effect on adenylate cyclase activity in the absence of any added hormone?

b) If you add an factor that increases the rate of GTPase hydrolysis of the Gs protein, will this activate or inhibit the observed downstream effect upon addition of the hormone (this is in the absence of GTP analogs or toxin). Explain your answer.

Explanation / Answer

A) Different inhibitory effect of adrenaline on platelet adenylate cyclase in the presence of GTP plus cholera toxin and of stable GTP analogues

GTP is generally required for hormonal stimulation of adenylate cyclase. On the other hand, the presence of GTP is essential for hormone-induced inhibition of adenylate cyclase in cell-free preparations of human platelets and other cells. In order to differentiate the dual roles of GTP in hormonal stimulation and inhibition of adenylate cyclase, we have studied the effect of adrenaline on the platelet enzyme under conditions where guanine mucleotides caused marked stimulation. In the presence of GTP (?1 ?M), which by itself had no or only a small stimulatory effect on adenylate cyclase, adrenaline inhibited the basal and prostaglandin E1-stimulated forms of the enzyme. In contrast, the stable GTP analogues, GMP-P(NH)P and GTP-?-S, which caused a time-dependent, persistent activation of the enzyme, reversed or prevented the inhibitory effect of adrenaline. Cholera toxin, which activates adenylate cyclase presumably by inhibition of a specific GTPase, increased cyclase activity in platelet membranes up to 4-fold, and GTP addition (0.1

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