Presynaptic BK channels control transmitter release: Physiological relevance and potential therapeutic implications

Abstract

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 Ca²⁺ 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 (Ca_v) 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 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 dysfunctions have been implicated in several neurological disorders including epilepsy, schizophrenia, Fragile X syndrome, mental retardation and autism. In particular, two mutations, in the α and in the β3 subunits, respectively, resulting in a gain of function, have been associated with epilepsy. Hence, these discoveries have allowed identifying BK channels as new drug targets for therapeutic intervention.

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