Low pHo boosts burst firing and catecholamine release by blocking TASK-1 and BK channels while preserving Cav1 channels in mouse chromaffin cells

Abstract

Mouse chromaffin cells (MCCs) generate action potential (AP) firing that regulates the Ca²⁺-dependent release of catecholamines (CAs). Recent findings indicate that MCCs possess a variety of spontaneous firing modes that span from the common "tonic-irregular" to the less frequent "burst" firing. This latter is evident in a small fraction of MCCs but occurs regularly when Nav1.3/1.7 channels are made less available or when the Slo1β2-subunit responsible for BK channel inactivation is deleted. Burst firing causes massive increases of Ca²⁺-entry and potentiates CA release ∼3.5-fold and, thus, may be a key mechanism to regulate MCC function. With the purpose of uncovering a physiological role for burst firing in CCs, we studied the effects of acidosis on MCCs activity. We found that lowering extracellular pH (pHo) from 7.4 to 7.0 and 6.6 induces 10–15 mV cell depolarizations that generate repeated bursts. Bursts at pHo 6.6 lasted ∼330 ms, occurred at 1–2 Hz and caused ∼7-fold increase of CA cumulative release. Burst firing originates from the inhibition of the pH-sensitive TASK-1/TASK-3 channels and from a 40% BK channel conductance reduction at pHo 7.0. The same pHo had little or no effect on Nav, Cav, Kv and SK channels that support AP firing in MCCs. Burst firing of pHo 6.6 could be mimicked by mixtures of the TASK-1 blocker A1899 (300 nM) and BK blocker paxilline (300 nM) and could be prevented by blocking L-type channels by adding 3 μm nifedipine. Mixtures of the two blockers raised cumulative CA-secretion even more than low-pHo (∼12-fold), showing that the action of protons on vesicle release is mainly due to the ionic conductance changes that increase Ca²⁺-entry during bursts. Our data furnish direct evidence that MCCs respond to low-pHo with sustained depolarization, burst firing and enhanced CA-secretion, thus mimicking the physiological response of CCs to acute acidosis and hyperkalemia generated during heavy exercise and muscle fatigue.

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