Calcium Channel CaV2.3 Subunits Regulate Hepatic Glucose Production by Modulating Leptin-Induced Excitation of Arcuate Pro-opiomelanocortin Neurons

Cell Rep. 2018 Oct 9;25(2):278-287.e4. doi: 10.1016/j.celrep.2018.09.024.

Abstract

Leptin acts on hypothalamic pro-opiomelanocortin (POMC) neurons to regulate glucose homeostasis, but the precise mechanisms remain unclear. Here, we demonstrate that leptin-induced depolarization of POMC neurons is associated with the augmentation of a voltage-gated calcium (CaV) conductance with the properties of the "R-type" channel. Knockdown of the pore-forming subunit of the R-type (CaV2.3 or Cacna1e) conductance in hypothalamic POMC neurons prevented sustained leptin-induced depolarization. In vivo POMC-specific Cacna1e knockdown increased hepatic glucose production and insulin resistance, while body weight, feeding, or leptin-induced suppression of food intake were not changed. These findings link Cacna1e function to leptin-mediated POMC neuron excitability and glucose homeostasis and may provide a target for the treatment of diabetes.

Keywords: POMC neuron; calcium channel; diabetes; glucose; hypothalamus; insulin resistance; leptin; liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Channels, R-Type / genetics
  • Calcium Channels, R-Type / metabolism*
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Cells, Cultured
  • Glucose / metabolism*
  • Homeostasis
  • Humans
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Leptin / pharmacology*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / metabolism*
  • Pro-Opiomelanocortin / metabolism*

Substances

  • Cacna1e protein, mouse
  • Calcium Channels, R-Type
  • Cation Transport Proteins
  • Leptin
  • Pro-Opiomelanocortin
  • Glucose
  • Calcium