K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons

Abstract

The selective degeneration of dopaminergic (DA) midbrain neurons in the substantia nigra (SN) is a hallmark of Parkinson disease. DA neurons in the neighboring ventral tegmental area (VTA) are significantly less affected. The mechanisms for this differential vulnerability of DA neurons are unknown. We identified selective activation of ATP-sensitive potassium (K-ATP) channels as a potential mechanism. We show that in response to parkinsonism-inducing toxins, electrophysiological activity of SN DA neurons, but not VTA DA neurons, is lost owing to activation of K-ATP channels. This selective K-ATP channel activation is controlled by differences in mitochondrial uncoupling between SN and VTA DA neurons. Genetic inactivation of the K-ATP channel pore-forming subunit Kir6.2 resulted in a selective rescue of SN but not VTA DA neurons in two mechanistically distinct mouse models of dopaminergic degeneration, the neurotoxicological 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model and the mutant weaver mouse. Thus, K-ATP channel activation has an unexpected role in promoting death of DA neurons in chronic disease.

Iptakalim Alleviates Rotenone-Induced Degeneration of Dopaminergic Neurons through Inhibiting Microglia-Mediated Neuroinflammation

“…Thus, mitoK ATP channels may be an important molecular target for inhibiting microglia-mediated neuroinflammation and for treating neuroinflammation-related neurodegenerative disorders. Although Liss et al (2005) reported that genetic inactivation of Kir6.2 resulted in a selective rescue of substantia nigra dopaminergic neurons in a MPTP model of dopaminergic degeneration, there were a large number of evidences for benefits afforded by activating mitoK ATP in ischemia and degeneration (Yamauchi et al, 2003;Busija et al, 2004;Farkas et al, 2005a, b). This discrepancy may be owing to the difference between the opening of mitoK ATP channels and genetic inactivation of Kir6.2.…”

“…This discrepancy may be owing to the difference between the opening of mitoK ATP channels and genetic inactivation of Kir6.2. In addition, the K ATP channels in dopaminergic neurons composed of Kir6.2 and SUR1 subunits display a promotion of neurodegenerative process in PD (Liss et al, 2005;Deutch and Winder, 2006), but it is worth noting that the composing subunits of K ATP channels in microglia differ from that of dopaminergic neurons and may play a distinct role in the initiation and process in the degenerative diseases.…”

“…Rotenone, a classic and high-affinity inhibitor of mitochondrial complex I, can induce selective dopamine neurons degeneration in substantia nigra (Helmuth, 2000;Jenner, 2001;Alam and Schmidt, 2002), and K ATP channel is considered as a potential downstream target of mitochondrial complex I inhibition (Liss et al, 2005). It is notable that microglial activation and subsequent inflammatory process induced by rotenone have been suggested to be the predominant mechanisms for degeneration of dopaminergic neurons in vivo and in vitro (Gao et al, 2002(Gao et al, , 2003aPerier et al, 2003;Sherer et al, 2003).…”

KATP Channel Openers Facilitate Glutamate Uptake by GluTs in Rat Primary Cultured Astrocytes

“…Activation of post-synaptic K ATP channels causes membrane hyperpolarization, which limits neuronal excess excitation; activation of presynaptic K ATP channels can directly modulate neurotransmitter release from nerve terminals. Therefore, K ATP channel openers (KCOs) serve as efficient tools that can adjust cell excitability, and exhibit beneficial effects under pathological conditions such as ischemia, stroke, and neurodegenerative diseases (Yao and Gross, 1994;Sargent et al, 1993;Liss et al, 2005). Emerging evidence including from our laboratory has revealed that the opening of K ATP channels play dominant protective roles in various models of neurodegenerative diseases such as Parkinson's disease (PD) (Tai et al, 2003;Wang et al, 2006;Yang et al, 2004).…”

Effect of inhibitors of NADPH oxidase complex and mitochondrial ATP‐sensitive potassium channels on generation of dopaminergic neurons from neurospheres of mesencephalic precursors

“…The structure of the pKATP channels has been studied extensively, and consists of multimeric proteins composed of inwardly rectifying-poreforming Kir6.x (Kir6.1/Kir6.2) and regulatorysulfonylurea receptor subunits (SUR1/ SUR/2). The presence pKATP channels in DAergic cells has been demonstrated in several studies (Liss and Roeper, 2001;Liss et al, 2005).…”