title: 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.
authors: Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo, Japan. yagami@himeji-du.ac.jp
authors: T
authors: T
authors: Yagami
authors: H
authors: H
authors: Kohma
authors: Y
authors: Y
authors: Yamamoto
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000378:metabolism; D003704:Dementia / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D018377:Neurotransmitter Agents / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018377:Neurotransmitter Agents; D002118:Calcium