L-type Ca2+ channel function during Timothy syndrome

Trends Cardiovasc Med. 2012 Apr;22(3):72-6. doi: 10.1016/j.tcm.2012.06.015.


Voltage-gated, dihydropyridine-sensitive L-type Ca(2+) channels are multimeric proteins composed of a pore-forming transmembrane α(1) subunit (Ca(v)1.2) and accessory β, α(2)δ, and γ subunits. Ca(2+) entry via Ca(v)1.2 channels shapes the action potential (AP) of cardiac myocytes and is required for excitation-contraction coupling. Two de novo point mutations of Ca(v)1.2 glycine residues, G406R and G402S, cause a rare multisystem disorder called Timothy syndrome (TS). Here, we discuss recent work on the mechanisms by which Ca(v)1.2 channels bearing TS mutations display slowed inactivation that leads to increased Ca(2+) influx, prolonging the cardiac AP and promoting lethal arrhythmias. Based on these studies, we propose a model in which the scaffolding protein AKAP79/150 stabilizes the open conformation of Ca(v)1.2-TS channels and facilitates physical interactions among adjacent channels via their C-tails, increasing the activity of adjoining channels and amplifying Ca(2+) influx.

Publication types

  • Review

MeSH terms

  • Autistic Disorder
  • Calcium Channels, L-Type*
  • Channelopathies / pathology*
  • Humans
  • Long QT Syndrome / genetics
  • Long QT Syndrome / pathology*
  • Mutation
  • Myocytes, Cardiac
  • Syndactyly / genetics
  • Syndactyly / pathology*


  • Calcium Channels, L-Type

Supplementary concepts

  • Timothy syndrome