Griguoli Marilena, Sgritta Martina, Cherubini Enrico
European Brain Research Institute (EBRI) 'Fondazione Rita Levi-Montalcini', Via del Fosso di Fiorano 64, 00143, Rome, Italy.
International School for Advanced Studies (SISSA), Trieste, Italy.
J Physiol. 2016 Jul 1;594(13):3489-500. doi: 10.1113/JP271841. Epub 2016 May 29.
BK channels are large conductance potassium channels characterized by four pore-forming α subunits, often co-assembled with auxiliary β and γ subunits to regulate Ca(2+) sensitivity, voltage dependence and gating properties. Abundantly expressed in the CNS, they have the peculiar characteristic of being activated by both voltage and intracellular calcium rise. The increase in intracellular calcium via voltage-dependent calcium channels (Cav ) during spiking triggers conformational changes and BK channel opening. This narrows the action potential and induces a fast after-hyperpolarization that shuts calcium channels. The tight coupling between BK and Cav channels at presynaptic active zones makes them particularly suitable for regulating calcium entry and neurotransmitter release. While in most synapses, BK channels exert a negative control on transmitter release under basal conditions, in others they do so only under pathological conditions, serving as an emergency brake to protect against hyperactivity. In particular cases, by interacting with other channels (i.e. limiting the activation of the delayed rectifier and the inactivation of Na(+) channels), BK channels induce spike shortening, increase in firing rate and transmitter release. Changes in transmitter release following BK channel dysfunction have been implicated in several neurological disorders including epilepsy, schizophrenia, fragile X syndrome, mental retardation and autism. In particular, two mutations, one in the α and one in the β3 subunit, resulting in a gain of function have been associated with epilepsy. Hence, these discoveries have allowed identification of BK channels as new drug targets for therapeutic intervention.
BK通道是一种大电导钾通道，其特征是由四个形成孔道的α亚基组成，通常与辅助性β和γ亚基共同组装，以调节Ca(2+)敏感性、电压依赖性和门控特性。它们在中枢神经系统中大量表达，具有被电压和细胞内钙升高激活的独特特性。在动作电位发放期间，通过电压依赖性钙通道（Cav）使细胞内钙增加，触发构象变化并打开BK通道。这会使动作电位变窄，并诱导快速的超极化后电位，从而关闭钙通道。BK通道与突触前活动区的Cav通道紧密耦合，使其特别适合调节钙内流和神经递质释放。在大多数突触中，BK通道在基础条件下对递质释放发挥负性调控作用，而在其他突触中，它们仅在病理条件下起作用，充当防止过度活动的紧急制动器。在特定情况下，通过与其他通道相互作用（即限制延迟整流器的激活和Na(+)通道的失活），BK通道可诱导动作电位缩短、发放频率增加和递质释放增加。BK通道功能障碍后递质释放的变化与多种神经系统疾病有关，包括癫痫、精神分裂症、脆性X综合征、智力迟钝和自闭症。特别是，α亚基和β3亚基中的两个突变导致功能增强，与癫痫有关。因此，这些发现已使BK通道被确定为治疗干预的新药物靶点。
