Adenyl cyclase protein inhibitor

G, is the G-protein responsible for inhibiting adenylate cyclase. The inhibition is mediated by the a subunit. Unlike Gs, G, is not affected by CTx but instead is ADP-ribosylated (and inhibited) by PTx. Of the three isoforms of G, (Gn 3), an is the most potent inhibitor of cyclase. G, also activates inward-rectifier (Kir3.1/3.2 and Kir 3.1/3.4) K+ channels (GIRK channels), and this activation is mediated by released f v subunits (see below). 

Other protein kinases may indirectly influence the activation of NF-kappap. For example, in contrast to the pro-inflammatory effects typically observed with activation of kinases, the elevation ofcAMP activates PKA and blocks transcription of iNOS mRNA [51,178, 229, 230]. Astrocytes contain a variety of NT receptors that are coupled to Gs-adenylate cyclase [231] and, either activation of P-adrenergic/dopamine receptors or employing agents that increase cAMP, such as forskolin (adenylate cyclase activator), PDE inhibitors [i.e. pentoxifylline], dibutyrl cAMP, or 8-bromo cAMP can attenuate lipopolysaccharide (LPS)/cytokine activated iNOS mRNA in microglia, astrocytes and a number of other cell types [51,176,177,178, 232-237]. In contrast, agents that suppress the intracellular concentration of cAM P such as H-89 and Rp-cAM P are pro-... 

In all cases the cells also utilize cAMP as an internal second messenger. For D. discoideum the components of the chemotactic-aggregation system include a 41-kDa cAMP receptor on the outside, adenylate cyclase, an extracellular diesterase that specifically hydrolyzes the cAMP to AMP, and a diesterase inhibitor protein.35 227-230 The inhibitor keeps the phosphodiesterase largely inactive initially, but when cAMP concentrations build up synthesis of the inhibitor is repressed and the cAMP is hydrolyzed, a necessary condition for retaining sensitivity of the receptors for the arriving pulses of cAMP. 

It is well know that /3-adrenoceptors couple to adenylate cyclases to activate a protein kinase A (PKA), but no direct evidence exists for the involvement of the /3-adrenoceptor-PKA signaling pathway in the affective component of pain. Thus, we examined the effect of intra-vBNST administration of a selective PKA inhibitor on isoproterenol- and pain-induced aversion. CPA induced by the intra-vBNST injection of isoproterenol was reversed by the coinjection of Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS), a selective PKA inhibitor. Furthermore, intra-vBNST injection of Rp-cAMPS dose-dependently attenuated the F-CPA. These data suggest that PKA activation within the vBNST via the enhancement of /3-adrenergic transmission is important for the negative affective component of pain (Fig. 3). 

Therapeutic approaches directed at the CFTR channel protein are also being considered. Elucidation of the mechanism of action of the CFTR has also led to the initiation of pharmacological strategies to correct the basic defect in CFTR. Elevation of intracellular cAMP has been shown to activate many mutant forms of CFTR. Thus, agents which increase cAMP levels by stimulating adenyl cyclase or inhibiting phosphodiesterases would be useful in therapy. Similarly, phosphatase inhibitors, which increase the net phosphate groups on the CFTR, may also be useful in therapy (Collins, 1992). 

There is also a Gi protein which is activated by a different set of receptors and has the opposite effect from the Gs protein in that it inhibits adenylate cyclase. As a result, the secondary messenger process is under the dual control of brake and accelerator and this explains the process by which two different neurotransmitters can have opposing effects at a target cell. A neurotransmitter which stimulates the production of a secondary messenger will form a receptor/ligand complex which activates the Gs protein, whereas a neurotransmitter which acts as an inhibitor will fit a different receptor which activates the G protein. 

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