T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome

Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11268-73. doi: 10.1073/pnas.1100869108. Epub 2011 Jun 20.

Abstract

The symptoms of irritable bowel syndrome (IBS) include significant abdominal pain and bloating. Current treatments are empirical and often poorly efficacious, and there is a need for the development of new and efficient analgesics aimed at IBS patients. T-type calcium channels have previously been validated as a potential target to treat certain neuropathic pain pathologies. Here we report that T-type calcium channels encoded by the Ca(V)3.2 isoform are expressed in colonic nociceptive primary afferent neurons and that they contribute to the exaggerated pain perception in a butyrate-mediated rodent model of IBS. Both the selective genetic inhibition of Ca(V)3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of Ca(V)3.2 channels into primary sensory neuron membranes, likely via a posttranslational effect. The butyrate-mediated regulation can be recapitulated with recombinant Ca(V)3.2 channels expressed in HEK cells and may provide a convenient in vitro screening system for the identification of T-type channel blockers relevant to visceral pain. These results implicate T-type calcium channels in the pathophysiology of chronic visceral pain and suggest Ca(V)3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Butyrates / toxicity
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, T-Type / deficiency
  • Calcium Channels, T-Type / genetics
  • Calcium Channels, T-Type / physiology*
  • Colon / innervation*
  • Colon / physiopathology*
  • Disease Models, Animal
  • Electrophysiological Phenomena
  • Gene Knockdown Techniques
  • Irritable Bowel Syndrome / chemically induced
  • Irritable Bowel Syndrome / drug therapy
  • Irritable Bowel Syndrome / physiopathology*
  • Male
  • Neuralgia / drug therapy
  • Neuralgia / physiopathology
  • Nociceptors / physiology
  • Pain Perception / physiology
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Butyrates
  • Cacna1h protein, rat
  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • RNA, Small Interfering