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The Journal of Neuroscience, November 29, 2006, 26(48):12602-12608; doi:10.1523/JNEUROSCI.4020-06.2006
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Cellular/Molecular
Rapid Activation of Inwardly Rectifying Potassium Channels by Immobile G-Protein-Coupled Receptors
Robert M. Lober, Miguel A. Pereira, andNevin A. Lambert Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30809
Correspondence should be addressed to Nevin A. Lambert, Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30809. Email: nlambert{at}mcg.edu
G-protein-coupled receptors (GPCRs) mediate slow synaptic transmission and many other effects of small molecule and peptide neurotransmitters. In the standard model of GPCR signaling, receptors and G-proteins diffuse laterally within the plane of the plasma membrane and encounter each other by random collision. This model predicts that signaling will be most efficient if both GPCRs and G-proteins are free to diffuse, thus maximizing collision frequency. However, neuronal GPCRs are often recruited to and enriched at specific synaptic locations, suggesting receptor mobility is restricted in these cells. Here, we test the hypothesis that restricting GPCR mobility impairs signaling in neurons by limiting the frequency of collisions between receptors and G-proteins. µ-Opioid receptors (MORs) were immobilized on the surface of cerebellar granule neurons by avidin-mediated cross-linking, and inwardly rectifying potassium (GIRK) channels were used as rapid indicators of G-protein activation. Mobile and immobile MORs activated GIRK channels with the same onset kinetics and agonist sensitivity in these neurons. In a heterologous expression system, GFP (green fluorescent protein)-tagged G
oA subunits remained mobile after cross-linking, but their mobility was reduced in the presence of immobile MORs, suggesting that these receptors and subunits were transiently precoupled. In addition, channel activation could be reconstituted with immobile GPCRs, G-protein heterotrimers, and GIRK channels. These results show that collision frequency is not rate-limiting for G-protein activation in CNS neurons, and are consistent with the idea that signaling components are compartmentalized or preassembled.
Key words: GPCR; GIRK channels; metabotropic; diffusion; µ-opioid receptor; G-protein
Received May 23, 2006; revised Oct. 27, 2006; accepted Oct. 31, 2006.
Correspondence should be addressed to Nevin A. Lambert, Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30809. Email: nlambert{at}mcg.edu
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