beta(1)-Subunit of BK channels regulates arterial wall[Ca(2+)] and diameter in mouse cerebral arteries.
Mice with a disrupted beta(1) (BK beta(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 beta(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 microM) or iberiotoxin (100 nM) increased [Ca(2+)](i) by approximately 75 nM and constricted +/+ BK beta(1) wild-type arteries (pressurized to 60 mmHg) with myogenic tone by approximately 10 microm. In contrast, ryanodine (10 microM) or iberiotoxin (100 nM) had no significant effect on [Ca(2+)](i) and diameter of -/- BK beta(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 beta(1) disrupts this negative feedback mechanism, leading to increased arterial tone through an increase in global [Ca(2+)](i).
Löhn
M
M
Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Charité University Hospitals, Humboldt University of Berlin, D-13125 Berlin, Germany.
Lauterbach
B
B
Haller
H
H
Pongs
O
O
Luft
F C
FC
Gollasch
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D002536:Cerebral Arteries / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000502:physiology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated; D012433:Ryanodine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D012433:Ryanodine; C064719:iberiotoxin; D002118:Calcium