Alternative sulfonylurea receptor expression defines metabolic sensitivity of K-ATP channels in dopaminergic midbrain neurons

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Abstract
ATP‐sensitive potassium (K‐ATP) channels couple the metabolic state to cellular excitability in various tissues. Several isoforms of the K‐ATP channel subunits, the sulfonylurea receptor (SUR) and inwardly rectifying K channel (Kir6.X), have been cloned, but the molecular composition and functional diversity of native neuronal K‐ATP channels remain unresolved. We combined functional analysis of K‐ATP channels with expression profiling of K‐ATP subunits at the level of single substantia nigra (SN) neurons in mouse brain slices using an RT–multiplex PCR protocol. In contrast to GABAergic neurons, single dopaminergic SN neurons displayed alternative co‐expression of either SUR1, SUR2B or both SUR isoforms with Kir6.2. Dopaminergic SN neurons expressed alternative K‐ATP channel species distinguished by significant differences in sulfonylurea affinity and metabolic sensitivity. In single dopaminergic SN neurons, co‐expression of SUR1 + Kir6.2, but not of SUR2B + Kir6.2, correlated with functional K‐ATP channels highly sensitive to metabolic inhibition. In contrast to wild‐type, surviving dopaminergic SN neurons of homozygous weaver mouse exclusively expressed SUR1 + Kir6.2 during the active period of dopaminergic neurodegeneration. Therefore, alternative expression of K‐ATP channel subunits defines the differential response to metabolic stress and constitutes a novel candidate mechanism for the differential vulnerability of dopaminergic neurons in response to respiratory chain dysfunction in Parkinson's disease.