A HUMAN CALCIUM-ACTIVATED POTASSIUM CHANNEL GENE EXPRESSED IN VASCULAR SMOOTH-MUSCLE

Large-conductance Ca2+-activated K+ (BK) channels are widespread and f unctionally heterogeneous. In other classes of K+ channels, functional heterogeneity derives from large gene families, alternative splicing, heterologous subunit composition, and functional modulation. The mole cular basis of mammalian BK channel heterogeneity is unknown, since on ly a single gene (mSlo) has been identified. BK channels in native vas cular smooth muscle have an apparent Ca2+ sensitivity similar to 10-fo ld greater than native brain or skeletal muscle channels, or cloned mS lo channels. Using mSlo as a low-stringency probe, we screened human a rterial smooth muscle and genomic libraries extensively in search of g enes or splice variants with novel properties. We isolated the human h omologue of mSlo, including two novel splice variant forms, but found no other related genes. Electrophysiological characterization of the h Slo clones in Xenopus oocytes and Chinese hamster ovary cells gave BK currents that were not measurably different from mSlo currents. Howeve r, coexpression of hSlo with a recently cloned beta-subunit derived fr om smooth muscle dramatically increased apparent Ca2+ sensitivity. Thu s alpha-subunits alone may not determine Ca2+ sensitivity of vascular smooth muscle BK channels. hSlo was mapped to human chromosome 10q23.1 , and the genomic structure was analyzed. Immediately after the amino terminal, two unusual regions of trinucleotide repeating sequences are present. The first of these regions encodes polyglycine, and the seco nd encodes polyserine. Both regions of repeated sequence are conserved between the mouse and human genome.