Published online before print August 16, 2001, doi: 10.1161/hh1701.095632
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© 2001 American Heart Association, Inc.
Cellular Biology |
O2 Modulates Large-Conductance Ca2+-Dependent K+ Channels of Rat Chemoreceptor Cells by a Membrane-Restricted and CO-Sensitive Mechanism
From the Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y Consejo superior de investigaciones científicas (CSIC), Dpto de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Valladolid, Spain.
Correspondence to José Ramón López-López, Dpto de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, C/Ramón y Cajal 7, 47005 Valladolid Spain. E-mail jrlopez{at}ibgm.uva.es
Hypoxic inhibition of large-conductance Ca2+-dependent K+ channels (maxiK) of rat carotid body type I cells is a well-established fact. However, the molecular mechanisms of such inhibition and the role of these channels in the process of hypoxic transduction remain unclear. We have examined the mechanisms of interaction of O2 with maxiK channels exploring the effect of hypoxia on maxiK currents recorded with the whole-cell and the inside-out configuration of the patch-clamp technique. Hypoxia inhibits channel activity both in whole-cell and in excised membrane patches. This effect is strongly voltage- and Ca2+-dependent, being maximal at low [Ca2+] and low membrane potential. The analysis of single-channel kinetics reveals a gating scheme comprising three open and five closed states. Hypoxia inhibits channel activity increasing the time the channel spends in the longest closed states, an effect that could be explained by a decrease in the Ca2+ sensitivity of those closed states. Reducing maxiK channels with dithiothreitol (DTT) increases channel open probability, whereas oxidizing the channels with 2,2'-dithiopyridine (DTDP) has the opposite effect. These results suggest that hypoxic inhibition is not related with a reduction of channel thiol groups. However, CO, a competitive inhibitor of O2 binding to hemoproteins, fully reverts hypoxic inhibition, both at the whole-cell and the single-channel level. We conclude that O2 interaction with maxiK channels does not require cytoplasmic mediators. Such interaction could be mediated by a membrane hemoprotein that, as an O2 sensor, would modulate channel activity.
Key Words: hypoxia • Ca2+-activated K+ channels • maxiK • redox modulation • carotid body
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