CONTRIBUTION OF CA2-ACTIVATED K+ CHANNELS TO CENTRAL CHEMOSENSITIVITYIN CULTIVATED NEURONS OF FETAL-RAT MEDULLA()

Neurons in fetal rat medullary slices that exhibited spontaneous elect rical activity after blockade of synaptic transmission were investigat ed for their response to decreases in extracellular pH. Increases in [ H+] (induced either by fixed acid or increases in PCO2) induced a sign ificant increase in the frequency of action potentials, associated wit h a membrane depolarization, and/or increases in the slope of the inte rspike depolarization. In addition, CO2/H+ prolonged the repolarizing phase of action potentials and reduced the afterhyperpolarization, sug gesting that K+ channels were the primary site of CO2/H+ action. The t ype of K+ channel that was modulated by CO2/H+ was identified by appli cation of agents that inhibited Ca2+-activated K+ channels either dire ctly (tetraethylammonium chloride, TEA) or indirectly (Cd2+ ions) by i nhibiting Ca2+ influx. CO2/H+ effects on neuronal activity were abolis hed after application of these blockers. The contribution of Ca2+-acti vated K+ channels to H+ sensitivity of these neurons was confirmed fur ther in voltage-clamp experiments in which outward rectifying I-V curv es were recorded that revealed a zero current potential of -70 mV. CO2 /H+ induced a prominent reduction in outward currents and shifted the zero current potential to more positive membrane potentials (mean -63 mV). The CO2/H+-sensitive current reversed at -72 mV and was blocked b y external application of TEA. It is concluded that CO2/H+ exerts its stimulatory effects on fetal medullary neurons by inhibition of Ca2+ a ctivated K+ channels, either directly or indirectly, by blocking volta ge-dependent Ca2+ channels, which in turn results in a reduction of K efflux and in cell depolarization.