Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy

Acetylcholine excites many central and autonomic neurons through inhibition of M-channels. slowly activating, noninactivating voltage-gated potassium channels. We here provide information regarding the in vivo distribution an d biochemical characteristics of human brain KCNQ2 and KCNQ3, two channel s ubunits that form M-channels when expressed in vitro, and, when mutated, ca use the dominantly inherited epileptic syndrome, benign neonatal familial c onvulsions. KCNQ2 and KCNQ3 proteins are colocalized in a somatodendritic p attern on pyramidal and polymorphic neurons in the human cortex and hippoca mpus. Immunoreactivity for KCNQ2, but not KCNQ3, is also prominent in some terminal fields, suggesting a presynaptic role for a distinct subgroup of M -channels in the regulation of action potential propagation and neurotransm itter release. KCNQ2 and KCNQ3 can be coimmunoprecipitated from brain lysat es. Further, KCNQ2 and KCNQ3 are coassociated with tubulin and protein kina se A within a Triton X-100-insoluble protein complex. This complex is not a ssociated with low-density membrane rafts or with N-methyl-D-aspartate rece ptors, PSD-95 scaffolding proteins, or other potassium channels tested. Our studies thus provide a view of a signaling complex that may be important f or cognitive function as well as epilepsy. Analysis of this complex may she d light on the unknown transduction pathway linking muscarinic acetylcholin e receptor activation to M-channel inhibition.