Short-term desensitization of G-protein-activated, inwardly rectifying K+ (GIRK) currents in pyramidal neurons of rat neocortex.
Whole cell recordings from acutely isolated rat neocortical pyramidal cells were performed to study the kinetics and the mechanisms of short-term desensitization of G-protein-activated, inwardly rectifying K+ (GIRK) currents during prolonged application (5 min) of baclofen, adenosine, or serotonin. Most commonly, desensitization of GIRK currents was characterized by a biphasic time course with average time constants for fast and slow desensitization in the range of 8 and 120 s, respectively. The time constants were independent of the agonist used to evoke the current. The biphasic time course was preserved in perforated-patch recordings, indicating that neither component of desensitization is attributable to cell dialysis. Desensitization of GIRK currents displayed a strong heterologous component in that application of a second agonist substantially reduced the responsiveness to a test agonist. Fast desensitization, but not slow desensitization, was lost in cells loaded with GDP, suggesting that the hydrolysis cycle of G proteins might underlie the initial, rapid current decline. Hydrolysis of phosphatidylinositol biphosphate is an unlikely candidate underlying short-term desensitization, because both components of desensitization were preserved in the presence of the phospholipase C inhibitor U73122. We conclude that short-term desensitization does neither result from receptor downregulation nor from altered channel gating but might involve modifications of the G-protein-dependent pathway that serves to translate receptor activation into channel opening.
Sickmann
Thomas
T
Department of Physiology, University of Munich, D-80336 Munich, Germany.
Alzheimer
Christian
C
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019579:Neocortex / Q000187:drug effects / Q000502:physiology*; D015221:Potassium Channels / Q000819:agonists / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D013997:Time Factors
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D001418:Baclofen; D000241:Adenosine