期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 158, 期 2, 页码 521-531出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1476-5381.2009.00332.x
关键词
calcium-activated chloride currents; calcium-activated potassium currents; K(Ca)1; 1; K(Ca)2; 1; K(Ca)2; 3; mslo; vascular smooth muscle; iberiotoxin; 1-EBIO
资金
- National Institutes of Health [5RO1 HL-075477]
- National Center for Research Resources (NCRR)
- Center of Biomedical Research Excellence at the University of Nevada School of Medicine, Reno, NV [NCRR 5P20 RR15581]
- British Heart Foundation [PG/ 05/ 038]
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR015581] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL075477] Funding Source: NIH RePORTER
Background and purpose: Recent pharmacological studies have proposed there is a high degree of similarity between calcium-activated Cl- channels (CaCCs) and large conductance, calcium-gated K+ channels (K(Ca)1.1). The goal of the present study was to ascertain whether blockers of K(Ca)1.1 inhibited calcium-activated Cl- currents (I-ClCa) and if the pharmacological overlap between K(Ca)1.1 and CaCCs extends to intermediate and small conductance, calcium-activated K+ channels. Experimental approaches: Whole-cell Cl- and K+ currents were recorded from murine portal vein myocytes using the whole-cell variant of the patch clamp technique. CaCC currents were evoked by pipette solutions containing 500 nM free [Ca2+]. Key results: The selective K(Ca)1.1 blocker paxilline (1 mu M) inhibited I-ClCa by similar to 90%, whereas penitrem A (1 mu M) and iberiotoxin (100 and 300 nM) reduced the amplitude of I-ClCa by similar to 20%, as well as slowing channel deactivation. Paxilline also abolished the stimulatory effect of niflumic acid on the CaCC. In contrast, an antibody against the Ca2+-binding domain of murine K(Ca)1.1 had no effect on I-ClCa while inhibiting spontaneous K(Ca)1.1 currents. Structurally different modulators of small and intermediate conductance calcium-activated K+ channels (K(Ca)2.1 and K(Ca)2.3), namely 1-EBIO, (100 mu M); NS309, (1 mu M); TRAM-34, (10 mu M); UCL 1684, (1 mu M) had no effect on I-ClCa. Conclusions and implications: These data show that the selective K(Ca)1.1 blockers also reduce I-ClCa considerably. However, the pharmacological overlap that exists between CaCCs and K(Ca)1.1 does not extend to the calcium-binding domain or to other calcium-gated K+ channels.
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