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A1899, PK-THPP, ML365, and Doxapram Inhibit Endogenous TASK Channels and Excite Calcium Signaling in Carotid Body type-1 Cells

A1899, PK-THPP, ML365, and Doxapram Inhibit Endogenous TASK Channels and Excite Calcium Signaling in Carotid Body type-1 Cells

Peadar B O'Donohoe, Nicky Huskens, Philip J Turner, Jaideep J Pandit, Keith J Buckler

Physiol Rep. 2018 Sep;6(19):e13876.

PMID: 30284397

Abstract:

Sensing of hypoxia and acidosis in arterial chemoreceptors is thought to be mediated through the inhibition of TASK and possibly other (e.g., BKC 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 [Ca2+ ]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 [Ca2+ ]i . These [Ca2+ ]i responses were abolished in Ca2+ -free solution and greatly attenuated by Ni2+ (2 mM) suggesting that depolarization and voltage-gated Ca2+ -entry mediated the rise in [Ca2+ ]i. Doxapram (50 μmol/L), a respiratory stimulant, also inhibited type-1 cell TASK channel activity and increased [Ca2+ ]i. . We also tested the effects of combined inhibition of BKC a and TASK channels. TEA (5 mmol/L) slightly increased [Ca2+ ]i in the presence of PK-THPP and A1899. Paxilline (300 nM) and iberiotoxin (50 nmol/L) also slightly increased [Ca2+ ]i in the presence of A1899 but not in the presence of PK-THPP. In general [Ca2+ ]i responses to TASK inhibitors, alone or in combination with BKC a inhibitors, were smaller than the [Ca2+ ]i responses evoked by hypoxia. These data confirm that TASK channel inhibition is capable of evoking membrane depolarization and robust voltage-gated Ca2+ -entry but suggest that this, even with concomitant inhibition of BKC a channels, may be insufficient to account fully for the [Ca2+ ]i -response to hypoxia.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1332454075	PK-THPP		1332454-07-5	Price

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