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Ca²⁺- and Voltage-Dependent Gating of Ca²⁺- and ATP-Sensitive Cationic Channels in Brain Capillary Endothelium

Department of Medical Biochemistry, Semmelweis University, and Neurochemical Group of the Hungarian Academy of Sciences, Budapest, Hungary

Correspondence: Address reprint requests to László Csanády, Dept. of Medical Biochemistry, Semmelweis University, 1444 Budapest, Pf. 262., Hungary. Tel.: 36-1-266-2755 ext. 4023; Fax: 36-1-267-0031; E-mail: csanady{at}puskin.sote.hu.

Biophysical properties of the Ca²⁺-activated nonselective cation channel expressed in brain capillaries were studied in inside-out patches from primary cultures of rat brain microvascular endothelial cells. At -40 mV membrane potential, open probability (P_o) was activated by cytosolic [Ca²⁺] > 1 µM and was half-maximal at 20 µM. Increasing [Ca²⁺] stimulated opening rate with little effect on closing rate. At constant [Ca²⁺], P_o was voltage-dependent, and effective gating charge corresponded to 0.6 ± 0.1 unitary charges. Depolarization accelerated opening and slowed closing, thereby increasing apparent affinity for Ca²⁺. Within 1 min of excision, P_o declined to a lower steady state with decreased sensitivity toward activating Ca²⁺ when studied at a fixed voltage, and toward activating voltage when studied at a fixed [Ca²⁺]. Deactivated channels opened 5-fold slower and closed 10-fold faster. The sulfhydryl-reducing agent dithiotreitol (1 mM) completely reversed acceleration of closing rate but failed to recover opening rate. Single-channel gating was complex; distributions of open and closed dwell times contained at least four and five exponential components, respectively. The longest component of the closed-time distribution was markedly sensitive to both [Ca²⁺] and voltage. We conclude that the biophysical properties of gating of this channel are remarkably similar to those of large-conductance Ca²⁺-activated K⁺ channels.

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