Dworetzky S I, Boissard C G, Lum-Ragan J T, McKay M C, Post-Munson D J, Trojnacki J T, Chang C P, Gribkoff V K
Central Nervous System Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.
J Neurosci. 1996 Aug 1;16(15):4543-50. doi: 10.1523/JNEUROSCI.16-15-04543.1996.
A human homolog of the large-conductance calcium-activated potassium (BK) channel beta subunit (hSlobeta) was cloned, and its effects on a human BK channel (hSlo) phenotype are reported. Coexpression of hSlo and hSlobeta, in both oocytes and human embryonic kidney 293 cells, resulted in increased Ca2+ sensitivity, marked slowing of BK channel activation and relaxation, and significant reduction in slow inactivation. In addition, coexpression changed the pharmacology of the BK channel phenotype: hSlo-mediated currents in oocytes were more sensitive to the peptide toxin iberiotoxin than were hSlo + hSlobeta currents, and the potency of blockade by the alkaloid BK blocker tetrandrine was much greater on hSlo + hSlobeta- mediated currents compared with hSlo currents alone. No significant differences in the response to charybdotoxin or the BK channel opener NS1619 were observed. Modulation of BK channel activity by phosphorylation was also affected by the presence of the hSlobeta subunit. Application of cAMP-dependent protein kinase increased P(OPEN) of hSlo channels, but decreased P(OPEN)of most hSlo + hSlobeta channels. Taken together, these altered characteristics may explain some of the wide diversity of BK channel phenotypes observed in native tissues.
克隆出了大电导钙激活钾（BK）通道β亚基的人类同源物（hSlobeta），并报道了其对人类BK通道（hSlo）表型的影响。在卵母细胞和人胚肾293细胞中，hSlo与hSlobeta共表达均导致Ca2+敏感性增加、BK通道激活和松弛显著减慢以及慢失活显著减少。此外，共表达改变了BK通道表型的药理学特性：卵母细胞中hSlo介导的电流比hSlo + hSlobeta电流对肽毒素iberiotoxin更敏感，并且与单独的hSlo电流相比，生物碱BK阻滞剂粉防己碱对hSlo + hSlobeta介导电流的阻断效力要大得多。在对蝎毒素或BK通道开放剂NS1619的反应中未观察到显著差异。hSlobeta亚基的存在也影响了磷酸化对BK通道活性的调节。应用cAMP依赖性蛋白激酶可增加hSlo通道的P(OPEN)，但会降低大多数hSlo + hSlobeta通道的P(OPEN)。综上所述，这些改变的特性可能解释了在天然组织中观察到的BK通道表型的广泛多样性。
