Parkinson’s disease (PD) is a debilitating motor coordination disorder caused by degeneration of dopamine neurons in the substantia nigra (SN). The involvement of GIRK channels in Parkinson’s disease was first inferred from the weaver mouse132, where constitutively active GIRK2wv channels produce chronic depolarization and cell death in a subset of neurons in the brain22,133,134 mimicking the neuronal degeneration observed in Parkinson’s disease160. The gain-of-function phenotype in DA neurons of weaver mice is of clinical interest due to the progressive degeneration of DA neurons in the substantia nigra, while DA neurons in the VTA are spared in the early stages of the disease161. Interestingly, DA neurons of the SN express only GIRK2, which results in a gain of function, while DA neurons in the VTA coexpress GIRK2/GIRK3, which may produce a loss of function due to co-assembly with GIRK322,133. Other mechanisms of DA cell death in the weaver mouse have been proposed, however. One study has suggested that constitutively active GIRK2wv channels trigger activation of K-ATP (Kir6.2) channels in response to mild mitochondrial uncoupling in SNc DA neurons but not VTA
