Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic GMP is central to visual excitation in vertebrate retinal rod cells. Sodium channels in the plasma membrane of the outer segment are kept open in the dark by a high level of cGMP. Light closes these channels by activating an enzymatic cascade that leads to the rapid hydrolysis of cGMP. Photoexcited rhodopsin triggers transducin by catalyzing the exchange of GTP for bound GDP. The activated GTP-form of transducin then switches on the phosphodiesterase by overcoming an inhibitory constraint. The overall gain of this cascade is about 10(5). The cascade is turned off by the GTPase activity of transducin and by the action of rhodopsin kinase and arrestin. One of the challenges now is to delineate the interplay of cGMP, calcium ion, and phosphoinositides in excitation and adaptation. Transducin belongs to a family of signal-coupling proteins that includes the G proteins of the hormone-regulated adenylate cyclase cascade. The initial events in visual excitation in molluscs and arthropods are probably similar to those of vertebrates. The triggering of transducin by photoexcited rhodopsin is a recurring motif in visual transduction. The coming together of electrophysiology, biochemistry, and molecular genetics affords new opportunities in unraveling the molecular mechanism of visual transduction.
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PMID:Cyclic GMP cascade of vision. 242 11

The structural components involved in transduction of extracellular signals as diverse as a photon of light impinging on the retina or a hormone molecule impinging on a cell have been highly conserved. These components include a recognition unit or receptor (for example, the beta-adrenergic receptor (beta AR) for catecholamines or the 'light receptor' rhodopsin), a guanine nucleotide regulatory or transducing protein, and an effector enzyme (for example, adenylate cyclase or cyclic GMP phosphodiesterase). Molecular cloning has revealed that the beta AR shares significant sequence and three-dimensional homology with rhodopsin. The function of the beta AR is diminished by exposure to stimulatory agonists, leading to desensitization. Similarly, 'light adaptation' involves decreased coupling of photoactivated rhodopsin to cGMP phosphodiesterase activation. Both forms of desensitization involve receptor phosphorylation. The latter is mediated by a unique protein kinase, rhodopsin kinase, which phosphorylates only the light-bleached form of rhodopsin. An analogous enzyme (termed beta AR kinase or beta ARK) phosphorylates only the agonist-occupied beta AR. We report here that beta ARK is also capable of phosphorylating rhodopsin in a totally light-dependent fashion. Moreover, rhodopsin kinase can phosphorylate the agonist-occupied beta AR. Thus the mechanisms which regulate the function of these disparate signalling systems also appear to be similar.
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PMID:Light-dependent phosphorylation of rhodopsin by beta-adrenergic receptor kinase. 301 40

Mounting evidence suggests that the physiological function of the various subtypes of adrenergic receptors is controlled by phosphorylation/dephosphorylation reactions. It seems intuitively unlikely that this phenomenon will be limited simply to the adrenergic receptors, since these receptors share transmembrane signaling pathways with a host of other plasma membrane receptors. Different types of kinases appear to be involved. On the one hand, phosphorylation reactions may operate in a classical feedback regulatory sense. Thus, the cAMP-dependent protein kinase, once activated by a beta-agonist, can feedback-regulate the function of the receptors by phosphorylating and desensitizing them. Similarly, protein kinase C appears to be able to feedback-regulate the function of alpha 1-adrenergic receptors by phosphorylation. There may also be "cross talk" between the systems. Thus, protein kinase C, when stimulated by phorbols, is able to phosphorylate and desensitize the beta-adrenergic receptors. Moreover, very recently we have found that the cAMP-dependent protein kinase can phosphorylate the alpha 1-adrenergic receptors in vitro. These are examples of one transmembrane signaling system regulating the function of another. Perhaps most interestingly, it appears that there may be a previously unappreciated class of receptor kinases in the cytosol of cells. The first of these, which we have recently found and named beta-ARK, serves to phosphorylate only the agonist-occupied form of the beta-adrenergic receptor. As noted, it is somewhat analogous to the rhodopsin kinase. Such highly specific receptor kinases, which can phosphorylate only the agonist-occupied form of a receptor, represent a potentially elegant mechanism for controlling the function of receptors in a fashion which is linked to their physiological stimulation. How widespread such kinases are, and the actual roles which they play in regulating receptor function, remain to be determined. Finally, it should be stressed that although this review has focused on the regulatory role of receptor phosphorylation, it is by no means our intent to suggest that receptors are the only locus for physiological control of sensitivity to hormone and drug reaction. There is already evidence that guanine nucleotide regulatory proteins can be regulated, and it seems likely that each of the components of the system, including the adenylate cyclase, are likely to be involved in various forms of complex regulation. To date, however, the receptors represent that component of the system whose regulation we understand in the greatest detail.
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PMID:Regulation of adrenergic receptor function by phosphorylation. 302 10