Premium
Low pH o boosts burst firing and catecholamine release by blocking TASK‐1 and BK channels while preserving Cav1 channels in mouse chromaffin cells
Author(s) -
Guarina Laura,
Vandael David H. F.,
Carabelli Valentina,
Carbone Emilio
Publication year - 2017
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp273735
Subject(s) - bursting , nifedipine , chemistry , depolarization , biophysics , bk channel , extracellular , catecholamine , acidosis , electrophysiology , chromaffin cell , medicine , neuroscience , membrane potential , endocrinology , calcium , adrenal medulla , biochemistry , biology , organic chemistry
Key points Mouse chromaffin cells (MCCs) generate spontaneous burst‐firing that causes large increases of Ca 2+ ‐dependent catecholamine release, and is thus a key mechanism for regulating the functions of MCCs. With the aim to uncover a physiological role for burst‐firing we investigated the effects of acidosis on MCC activity. Lowering the extracellular pH (pH o ) from 7.4 to 6.6 induces cell depolarizations of 10–15 mV that generate bursts of ∼330 ms at 1–2 Hz and a 7.4‐fold increase of cumulative catecholamine‐release. Burst‐firing originates from the inhibition of the pH‐sensitive TASK‐1‐channels and a 60% reduction of BK‐channel conductance at pH o 6.6. Blockers of the two channels (A1899 and paxilline) mimic the effects of pH o 6.6, and this is reverted by the Cav1 channel blocker nifedipine. MCCs act as pH‐sensors. At low pH o , they depolarize, undergo burst‐firing and increase catecholamine‐secretion, generating an effective physiological response that may compensate for the acute acidosis and hyperkalaemia generated during heavy exercise and muscle fatigue.Abstract Mouse chromaffin cells (MCCs) generate action potential (AP) firing that regulates the Ca 2+ ‐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 large increases of Ca 2+ ‐entry and potentiates CA release by ∼3.5‐fold and thus may be a key mechanism for regulating MCC function. With the aim to uncover a physiological role for burst‐firing we investigated the effects of acidosis on MCC activity. Lowering the extracellular pH (pH o ) from 7.4 to 7.0 and 6.6 induces cell depolarizations of 10–15 mV that generate repeated bursts. Bursts at pH o 6.6 lasted ∼330 ms, occurred at 1–2 Hz and caused an ∼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 pH o 7.0. The same pH o had little or no effect on Nav, Cav, Kv and SK channels that support AP firing in MCCs. Burst firing of pH o 6.6 could be mimicked by mixtures of the TASK‐1 blocker A1899 (300 n m ) and BK blocker paxilline (300 n m ) and could be prevented by blocking L‐type channels by adding 3 μ m nifedipine. Mixtures of the two blockers raised cumulative CA‐secretion even more than low pH o (∼12‐fold), showing that the action of protons on vesicle release is mainly a result of the ionic conductance changes that increase Ca 2+ ‐entry during bursts. Our data provide direct evidence suggesting that MCCs respond to low pH o with sustained depolarization, burst firing and enhanced CA‐secretion, thus mimicking the physiological response of CCs to acute acidosis and hyperkalaemia generated during heavy exercise and muscle fatigue.