Activation of heterotrimeric G-proteins independent of a G-protein coupled receptor and the implications for signal processing
rgs proteins; beta-gamma-subunits; dissociation; asymmetric cell-division; g-alpha subunits; dynein light-chain; guanine-nucleotide exchange; ras-related protein; controls autophagic sequestration; gtp-binding proteins; inhibitor activity
Heterotrimeric G-proteins are key transducers for signal transfer from Outside the cell, mediating signals emanating from cell-surface G-protein coupled receptors (GPCR). Many, if not all, subtypes of heterotrimeric G-proteins are also regulated by accessory proteins that influence guanine nucleoide binding, guanosine triphosphate (GTP) hydrolysis, or Subunit interactions. One subgroup of such accessory proteins (activators of G-protein signaling; AGS proteins) refer to a functionally defined group of proteins that activate selected G-protein signaling systems in the absence of classical G-protein Coupled receptors. AGS and related proteins provide unexpected insights into the regulation of the G-protein activation-deactivation cycle. Different AGS proteins function as guanine nulcleotide exchange factors or guanine nucleotide dissociation inhibitors and may also influence subunit interactions by interaction with G beta gamma. These proteins play important roles in the generation or positioning of signaling complexes and of the regulation of GPCR signaling, and as alternative binding partners for G-protein subunits. Perhaps of even broader impact is the discovery that AGS proteins provide a foundation for the concept that heterotrimeric G-protein subunits are processing signals within the cell involving intrinsic Cues that do not involve the classical signal input from a cell surface GPCR.
Cismowski M J; Lanier S M
Reviews of Physiology Biochemistry and Pharmacology, Vol 155
2005
2005
Book Chapter
n/a
Changes of the responses of single sympathetic ganglionic neurones to substance P following desensitization
adenylate-cyclase; binding; cells; desensitization; G protein; inhibition; k+ current; kinase-c; M current; muscarine; Neurosciences & Neurology; Pharmacology & Pharmacy; phosphorylation; protein alpha-subunits; receptor; rgs proteins; Substance P
1 The neuropeptide substance P (SP) exerts an excitatory effect on sympathetic neurones by inhibiting a time- and voltage-dependent potassium current. During prolonged application of SP, the response desensitizes. The changes in kinetics of the SP response in single neurones after desensitization have been studied in an attempt to gain some insight as to the molecular mechanism of desensitization in live, functioning neurones. 2 Desensitization to SP resulted in subsequent SP responses being smaller, but the time course was unchanged in desensitized cells compared with non-desensitized cells. 3 Experimental manipulations were performed to decrease receptor and G protein function for comparison to desensitization. Intracellular application of GDP betaS, to decrease G protein function, led to successive responses to agonist becoming smaller and slower. When functional muscarinic receptors were decreased by extracellular application of propylbenzilylcholine mustard (PrBCM), the response to muscarine became smaller, but the time course was unchanged compared with the change in time course produced by PrBCM vehicle alone. 4 The results have also been compared with simulations from a mathematical model of drug-receptor-G protein interactions. Under a constrained set of conditions, the model predicts that decreasing the size of the G protein pool will decrease both the magnitude and the time course of the response to agonist. Decreasing receptor levels results in a more efficient decrease in the magnitude of the response but no change in the time course of the response. 5 These data provide evidence that desensitization of the response to SP in single neurones results from a decrease in functional receptors.
Simmons M A
Journal of Autonomic Pharmacology
2001
2001-04
Journal Article
<a href="http://doi.org/10.1046/j.1365-2680.2001.00214.x" target="_blank" rel="noreferrer noopener">10.1046/j.1365-2680.2001.00214.x</a>