CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes

Neuron. 2018 May 2;98(3):547-561.e10. doi: 10.1016/j.neuron.2018.03.043. Epub 2018 Apr 19.

Abstract

Binding of sweet, umami, and bitter tastants to G protein-coupled receptors (GPCRs) in apical membranes of type II taste bud cells (TBCs) triggers action potentials that activate a voltage-gated nonselective ion channel to release ATP to gustatory nerves mediating taste perception. Although calcium homeostasis modulator 1 (CALHM1) is necessary for ATP release, the molecular identification of the channel complex that provides the conductive ATP-release mechanism suitable for action potential-dependent neurotransmission remains to be determined. Here we show that CALHM3 interacts with CALHM1 as a pore-forming subunit in a CALHM1/CALHM3 hexameric channel, endowing it with fast voltage-activated gating identical to that of the ATP-release channel in vivo. Calhm3 is co-expressed with Calhm1 exclusively in type II TBCs, and its genetic deletion abolishes taste-evoked ATP release from taste buds and GPCR-mediated taste perception. Thus, CALHM3, together with CALHM1, is essential to form the fast voltage-gated ATP-release channel in type II TBCs required for GPCR-mediated tastes.

Keywords: ATP release; blue-native page; concatemer; hexamer; knockout; mouse; patch-clamp electrophysiology; single-molecule photobleaching; taste bud; voltage-gated.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels / analysis
  • Calcium Channels / physiology*
  • Female
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Ion Channel Gating / physiology*
  • Mice
  • Mice, Transgenic
  • Receptors, G-Protein-Coupled / analysis
  • Receptors, G-Protein-Coupled / physiology*
  • Receptors, Purinergic / analysis
  • Receptors, Purinergic / physiology*
  • Synaptic Transmission / physiology
  • Taste / physiology*
  • Taste Perception / physiology*
  • Xenopus

Substances

  • CALHM1 protein, mouse
  • Calcium Channels
  • Receptors, G-Protein-Coupled
  • Receptors, Purinergic