Loss of SUR1 and Kir6.2 ATP-sensitive potassium channel subunits produces comparable neuronal excitability and morphine antinociception

Abstract

ATP-sensitive potassium (KATP) channels are integral membrane proteins that play a crucial role in linking cellular metabolism to neuronal excitability. KATP channels in peripheral nociception and pain emphasize metabolic gating as a determinant of dorsal root ganglia and spinal cord excitability, particularly in pathophysiological states. Activation of KATP channels reduces excitability and and also contributes to opioid induced analgesia. KATP channels are composed of multiple subunits, that are assembled in several subtypes, including Kir6.2/SUR1 which is found predominantly in neurons in the nervous system. It remains unclear whether both Kir6.2 and SUR1 subunits are required to regulate neuronal excitability under naive conditions and to mediate morphine-induced antinociception. These experiments aim to determine whether neuron-specific loss of either Kir6.2 or SUR1 increases dorsal root ganglion (DRG) neuronal excitability, and attenuates morphine antinociception in mice. We found that loss of SUR1 or Kir6.2 activity or expression both increased DRG excitability in whole cell patch clamp studies. Using DRG cultured from SUR1 and Kir6.2 floxed animals, we also found that loss of either subunit decreased potassium flux induced by diazoxide. Morphine induced antinociception was also attenuated after Cre-mediated recombination in SUR1 and Kir6.2 floxed animals. Chronic morphine administration also decreased Kir6.2 (gene: Kcnj11) RNA signal in mouse DRG, but not spinal cords. Together, these findings suggest that, despite evidence from single-cell sequencing and other datasets indicating potentially distinct expression patterns of SUR1 and Kir6.2, these subunits most likely function cooperatively to form functional KATP channels under normal physiological conditions.