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

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.

journal_name

Curr Med Chem

authors

Yagami T,Kohma H,Yamamoto Y

doi

10.2174/092986712803341430

subject

Has Abstract

pub_date

2012-01-01 00:00:00

pages

4816-27

issue

28

eissn

0929-8673

issn

1875-533X

pii

CMC-EPUB-20120725-10

journal_volume

19

pub_type

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