{beta}1-subunit of BK channels regulates arterial wall [Ca2+] and diameter in mouse cerebral arteries

Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Charité University Hospitals, Humboldt University of Berlin, D-13125 Berlin; Institut für Neuronale Signalverarbeitung, ZMNH, University of Hamburg, D-20246 Hamburg; and Department of Nephrology, Medical School Hannover, D-30625 Hannover, Germany Mice with a disrupted 1 (BK 1 )-subunit of the large-conductance Ca 2+ -activated K + (BK) channel gene develop systemic hypertension and cardiac hypertrophy, which is likely caused by uncoupling of Ca 2+ sparks to BK channels in arterial smooth muscle cells. However, little is known about the physiological levels of global intracellular Ca 2+ concentration ([Ca 2+ ] i ) and its regulation by Ca 2+ sparks and BK channel subunits. We utilized a BK 1 knockout C57BL/6 mouse model and studied the effects of inhibitors of ryanodine receptor and BK channels on the global [Ca 2+ ] i and diameter of small cerebral arteries pressurized to 60 mmHg. Ryanodine (10 µM) or iberiotoxin (100 nM) increased [Ca 2+ ] i by ~75 nM and constricted +/+ BK 1 wild-type arteries (pressurized to 60 mmHg) with myogenic tone by ~10 µm. In contrast, ryanodine (10 µM) or iberiotoxin (100 nM) had no significant effect on [Ca 2+ ] i and diameter of / BK 1 -pressurized (60 mmHg) arteries. These results are consistent with the idea that Ca 2+ sparks in arterial smooth muscle cells limit myogenic tone through activation of BK channels. The activation of BK channels by Ca 2+ sparks reduces the voltage-dependent Ca 2+ influx and [Ca 2+ ] i through tonic hyperpolarization. Deletion of BK 1 disrupts this negative feedback mechanism, leading to increased arterial tone through an increase in global [Ca 2+ ] i . calcium; calcium-activated potassium channels; pressurized cerebral arteries; arterial tone; BK 1 knockout mouse