L-Type Voltage-Dependent Calcium Channels As Therapeutic Targets for Neurodegenerative Diseases

Author(s): T. Yagami, H. Kohma, Y. Yamamoto.

Journal Name: Current Medicinal Chemistry

Volume 19 , Issue 28 , 2012

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Abstract:

a2+ 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 Ca2+ from the extracellular fluid is required for sustained elevation of the cytosolic Ca2+ concentration and full activation of Ca2+-dependent processes. Voltage-dependent Ca2+ channels (VDCCs) serve as the principal routes of Ca2+ 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 Ca2+ 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 Ca2+ 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.

Keywords: L-type voltage-dependent Ca2+ channels, long-term potentiation, neurodegenerative diseases, vascular dementia, Alzheimer’s disease, phospholipase A2

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Article Details

VOLUME: 19
ISSUE: 28
Year: 2012
Page: [4816 - 4827]
Pages: 12
DOI: 10.2174/092986712803341430
Price: $58

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