Glutamate-activated BK channel complexes formed with NMDA receptors

Abstract

The large-conductance calcium- and voltage-activated K (BK) channel has a requirement of high intracellular free Ca concentrations for its activation in neurons under physiological conditions. The Ca sources for BK channel activation are not well understood. In this study, we showed by coimmunopurification and colocalization analyses that BK channels form complexes with NMDA receptors (NMDARs) in both rodent brains and a heterologous expression system. The BK-NMDAR complexes are broadly present in different brain regions. The complex formation occurs between the obligatory BKα and GluN1 subunits likely via a direct physical interaction of the former's intracellular S0-S1 loop with the latter's cytosolic regions. By patch-clamp recording on mouse brain slices, we observed BK channel activation by NMDAR-mediated Ca influx in dentate gyrus granule cells. BK channels modulate excitatory synaptic transmission via functional coupling with NMDARs at postsynaptic sites of medial perforant path-dentate gyrus granule cell synapses. A synthesized peptide of the BKα S0-S1 loop region, when loaded intracellularly via recording pipette, abolished the NMDAR-mediated BK channel activation and effect on synaptic transmission. These findings reveal the broad expression of the BK-NMDAR complexes in brain, the potential mechanism underlying the complex formation, and the NMDAR-mediated activation and function of postsynaptic BK channels in neurons.

Metabolomic and transcriptomic signatures of prenatal excessive methionine support nature rather than nurture in schizophrenia pathogenesis

“…Kcnma1 encodes the large-conductance calcium-activated potassium channel, subfamily M, alpha member 1 (BK channel) pore-forming alpha subunit, which is involved in neuronal excitability and plasticity, and has been associated with neurological and psychiatric disorders, including epilepsy autism and Alzheimer’s. While the activation of presynaptic BK channels decreases glutamate release 54 – 56 , the activation of postsynaptic BK, which couples to GluN1, suppress NMDA-potentiated evoked excitatory postsynaptic potentials (EPSP) 57 . Our results suggest that early upregulation of Kcnma1 channels might provoke sustained hypoactivity of excitatory pathways in the hippocampus (reducing glutamate release, and suppressing NMDA receptors).…”

GABAergic Input Affects Intracellular Calcium Levels in Developing Granule Cells of Adult Rat Hippocampus

“…It is known that BK channels in mature dentate granule cells form complexes with NMDA receptors [27], and this structural and functional coupling might also occur in immature neurons. In line with this, we found a robust BK current after local NMDA or glutamate application onto the recorded immature neurons, but ambient glutamate levels were not able to open NMDARs in our experimental conditions.…”

BK channel clustering is required for normal behavioral alcohol sensitivity in C. elegans

“…One possibility is that ethanol can activate both clustered and diffuse SLO-1 channels but only clustered SLO-1 channels are relevant to ethanol sensitivity due to their coupling with calcium channels that mediate behavioral sensitivity to ethanol. It has been reported that BK channels are functionally coupled with a wide variety of calcium channels 23–27 , which localize to distinct subcellular compartments, including pre- and post-synaptic sites, the ER, and muscle excitation sites 28,29 . Although clustered and diffuse SLO-1 channels both increase potassium efflux in response to ethanol, only clustered SLO-1 channels lead to an inhibition of behaviorally-relevant calcium channels, thereby causing sedation at the behavioral level.…”