Open AccessA1899, PK‐THPP, ML365, and Doxapram inhibit endogenous TASK channels and excite calcium signaling in carotid body type‐1 cells
Author(s) -
O'Donohoe Peadar B.,
Huskens Nicky,
Turner Philip J.,
Pandit Jaideep J.,
Buckler Keith J.
Publication year - 2018
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.13876
Subject(s) - depolarization , carotid body , calcium signaling , bk channel , doxapram , membrane potential , biophysics , chemistry , potassium channel , hyperpolarization (physics) , iberiotoxin , voltage dependent calcium channel , hypoxia (environmental) , calcium , pharmacology , medicine , endocrinology , biochemistry , biology , signal transduction , anatomy , electrophysiology , stereochemistry , oxygen , organic chemistry , nuclear magnetic resonance spectroscopy
Sensing of hypoxia and acidosis in arterial chemoreceptors is thought to be mediated through the inhibition of TASK and possibly other (e.g., BK C a ) potassium channels which leads to membrane depolarization, voltage‐gated Ca‐entry, and neurosecretion. Here, we investigate the effects of pharmacological inhibitors on TASK channel activity and [Ca 2+ ] i ‐signaling in isolated neonatal rat type‐1 cells. PK ‐ THPP inhibited TASK channel activity in cell attached patches by up to 90% (at 400 nmol/L). A1899 inhibited TASK channel activity by 35% at 400 nmol/L. PK ‐ THPP , A1899 and Ml 365 all evoked a rapid increase in type‐1 cell [Ca 2+ ] i . These [Ca 2+ ] i responses were abolished in Ca 2+ ‐free solution and greatly attenuated by Ni 2+ (2 mM ) suggesting that depolarization and voltage‐gated Ca 2+ ‐entry mediated the rise in [Ca 2+ ] i. Doxapram (50 μ mol/L), a respiratory stimulant, also inhibited type‐1 cell TASK channel activity and increased [Ca 2+ ] i. . We also tested the effects of combined inhibition of BK C a and TASK channels. TEA (5 mmol/L) slightly increased [Ca 2+ ] i in the presence of PK ‐ THPP and A1899. Paxilline (300 nM ) and iberiotoxin (50 nmol/L) also slightly increased [Ca 2+ ] i in the presence of A1899 but not in the presence of PK ‐ THPP . In general [Ca 2+ ] i responses to TASK inhibitors, alone or in combination with BK C a inhibitors, were smaller than the [Ca 2+ ] i responses evoked by hypoxia. These data confirm that TASK channel inhibition is capable of evoking membrane depolarization and robust voltage‐gated Ca 2+ ‐entry but suggest that this, even with concomitant inhibition of BK C a channels, may be insufficient to account fully for the [Ca 2+ ] i ‐response to hypoxia.