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BK channel ₁-subunit regulation of calcium handling and constriction in tracheal smooth muscle

Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas

Submitted 22 March 2006 ; accepted in final form 18 April 2006

The large-conductance, Ca²⁺-activated K⁺ (BK) channels are regulators of voltage-dependent Ca²⁺ entry in many cell types. The BK channel accessory ₁-subunit promotes channel activation in smooth muscle and is required for proper tone in the vasculature and bladder. However, although BK channels have also been implicated in airway smooth muscle function, their regulation by the ₁-subunit has not been investigated. Utilizing the gene-targeted mice for the ₁-subunit gene, we have investigated the role of the ₁-subunit in tracheal smooth muscle. In mice with the ₁-subunit-knockout allele, BK channel activity was significantly reduced in excised tracheal smooth muscle patches and spontaneous BK currents were reduced in whole tracheal smooth muscle cells. Knockout of the ₁-subunit resulted in an increase in resting Ca²⁺ levels and an increase in the sustained component of Ca²⁺ influx after cholinergic signaling. Tracheal constriction studies demonstrate that the level of constriction is the same with knockout of the ₁-subunit and BK channel block with paxillin, indicating that BK channels contribute little to airway relaxation in the absence of the ₁-subunit. Utilizing nifedipine, we found that the increased constriction caused by knockout of the ₁-subunit could be accounted for by an increased recruitment of L-type voltage-dependent Ca²⁺ channels. These results indicate that the ₁-subunit is required in airway smooth muscle for control of voltage-dependent Ca²⁺ influx during rest and after cholinergic signaling in BK channels.

airway; knockout mice; gene-targeted mice

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