Functional Coupling of BK Channels to NMDA Receptors in Hippocampal Dentate Gyrus

Abstract

The large conductance calcium- and voltage-activated potassium channel (BK channels) is widely expressed in the central nervous system. The physiological roles of BK channels and the calcium sources of their activation in mammalian brain remain not well-understood. Our proteomic and biochemical analyses of BK channels and the calcium-permeable NMDA receptors and have found that they form protein complexes in whole brain and various brain regions, consisting of the obligatory BK channel alpha-subunit and GluN1 subunits and at least the regulatory GluN2A and GluN2B subunits. We examined the functional coupling of BK channels to NMDA receptors in mice hippocampal dentate gyrus. We observed that glutamate evoked outward currents of BK channels in dentate gyrus granule cell soma at potentials more positive than −20 mV which were sensitive to BK channel-specific blocker paxilline and abolished by NMDA receptor antagonist AP-5. We also found that blockade of BK channels by paxilline increased the amplitude of excitatory postsynaptic potential (EPSP) of granule cells evoked by stimulation in the perforant path-granule cell synapses, which was prevented by the presence of AP-5. We thus inferred that BK channels were activated by NMDA receptor-mediated Ca2+ influx in hippocampal dentate gyrus granule cells and the calcium-mediated functional coupling between these two types of channels plays a role in regulation of synaptic transmission.