OPPOSING MECHANISMS OF REGULATION OF A G-PROTEIN-COUPLED INWARD RECTIFIER K-BRAIN NEURONS( CHANNEL IN RAT)

In locus coeruleus neurons, substance P (SP) suppresses an inwardly re ctifying K+ current via a pertussis toxin-insensitive guanine nucleoti de binding protein (G protein; G(nonPTX)), whereas somatostatin (SOM) or [Met]enkephalin (MENK) enhances it via a pertussis toxin-sensitive G protein (G(PTX)). The interaction of the SP and the SOM (or MENK) ef fects was studied in cultured locus coeruleus neurons. In neurons load ed with guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S]), applicat ion of SOM (or MENK) evoked a persistent increase in the inward rectif ier K+ conductance. A subsequent application of SP suppressed this con ductance to a level less than that before the SOM (or MENK) applicatio n; the final conductance level was independent of the magnitude of the SOM (or MENK) response. This suppression by SP was persistent, and a subsequent SOM (or MENK) application did not reverse it. When SP was a pplied to GTP[gamma S]-loaded cells first, subsequent SOM elicited onl y a small response. In GTP-loaded neurons, application of SP temporari ly suppressed the subsequent SOM- (or MENK)-induced conductance increa se. These results suggest that the same inward rectifier molecule that responds to an opening signal from G(PTX) also responds to a closing signal from G(nonPTX). The closing signal is stronger than the opening signal.