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WATER AND ELECTROLYTE HOMEOSTASIS

Small-conductance, Ca²⁺-activated K⁺ channel 2 is the key functional component of SK channels in mouse urinary bladder

¹Department of Pharmacology, University of Vermont, Burlington, Vermont; ²Urogenital Biology, Cardiovascular and Urogenital Center of Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania; and ³Vollum Institute, Oregon Health and Science University, Portland, Oregon

Submitted 3 November 2006 ; accepted in final form 10 March 2008

Small-conductance Ca²⁺-activated K⁺ (SK) channels play an important role in regulating the frequency and in shaping urinary bladder smooth muscle (UBSM) action potentials, thereby modulating contractility. Here we investigated a role for the SK2 member of the SK family (SK1-3) utilizing: 1) mice expressing β-galactosidase (β-gal) under the direction of the SK2 promoter (SK2 β-gal mice) to localize SK2 expression and 2) mice lacking SK2 gene expression (SK2^–/– mice) to assess SK2 function. In SK2 β-gal mice, UBSM staining was observed, but staining was undetected in the urothelium. Consistent with this, urothelial SK2 mRNA was determined to be 4% of that in UBSM. Spontaneous phasic contractions in wild-type (SK2^+/+) UBSM strips were potentiated (259% of control) by the selective SK channel blocker apamin (EC₅₀ = 0.16 nM), whereas phasic contractions of SK2^–/– strips were unaffected. Nerve-mediated contractions of SK2^+/+ UBSM strips were also increased by apamin, an effect absent in SK2^–/– strips. Apamin increased the sensitivity of SK2^+/+ UBSM strips to electrical field stimulation, since pretreatment with apamin decreased the frequency required to reach a 50% maximal contraction (vehicle, 21 ± 4 Hz, n = 6; apamin, 12 ± 2 Hz, n = 7; P < 0.05). In contrast, the sensitivity of SK2^–/– UBSM strips was unaffected by apamin. Here we provide novel insight into the molecular basis of SK channels in the urinary bladder, demonstrating that the SK2 gene is expressed in the bladder and that it is essential for the ability of SK channels to regulate UBSM contractility.

bladder; contractility; small-conductance calcium-activated potassium channel; apamin

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