L-type voltage-dependent calcium channels as therapeutic targets for neurodegenerative diseases

Curr Med Chem. 2012;19(28):4816-27. doi: 10.2174/092986712803341430.

Abstract

Ca(2+) is a highly versatile intracellular second messenger in the central nervous system, and regulates many complicated cellular processes, including excitation, plasticity and apoptosis. Influx of Ca(2+) from the extracellular fluid is required for sustained elevation of the cytosolic Ca(2+) concentration and full activation of Ca(2+)-dependent processes. Voltage-dependent Ca(2+) channels (VDCCs) serve as the principal routes of Ca(2+) entry into electrically excitable cells such as neurons. The nervous system expresses VDCCs with unique cellular and subcellular distribution and specific functions. L-type voltage-dependent Ca(2+) channels (L-VDCCs) are distributed at neuronal cell bodies, dendrites and spines, and the postsynaptic L-VDCCs regulate neuronal excitability and gene expression. Presynaptic P/Qand N-type VDCCs trigger neurotransmitter release, and T-type channels support neuronal rhythmic burst firing. Evidence from natural mutants, knockout mice, and human genetic disorders indicates a fundamental role of some VDCCs in a wide variety of neurological disorders, including vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD) and Prion disease. Amyloid β peptides, causative factors for AD, potentiate the influx of Ca(2+) into neurons via L-VDCCs. L-VDCCs blockers prevent neurons from undergoing amyloid β-induced apoptosis. The present review highlights some recent findings on biochemical characterizations, physiological functions, pathological roles and pharmacological applications of the L-VDCCs and their implication in neurologic diseases.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Calcium / metabolism
  • Calcium Channel Blockers / chemistry
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / chemistry*
  • Calcium Channels, L-Type / metabolism
  • Dementia / metabolism
  • Dementia / pathology
  • Humans
  • Ion Transport / drug effects
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology
  • Neurotransmitter Agents / metabolism
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Prion Diseases / metabolism
  • Prion Diseases / pathology
  • Risk Factors

Substances

  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Neurotransmitter Agents
  • Calcium