role of L-type voltage-gated calcium channels Caᵥ1.2 and Ca ᵥ1.3 in normal and pathological brain function

• Published in: Cell and tissue research 2014, Vol.357 (2), p.463-476
• Main Authors: Berger, Stefan M, Bartsch, Dusan
• Format: Article
• Language: English
• Subjects: amphetamine; brain; calcium; calcium channels; cocaine; deafness; dopamine; drug abuse; fearfulness; humans; memory; patients; rodents; synaptic transmission
• ISSN: 0302-766X; 1432-0878

The use of specific activators and inhibitors that penetrate the central nervous system has suggested an essential functional role of L-type calcium channels (LTCC) in several important physiological processes of the brain, including the modulation of the mesoaccumbal dopamine signalling pathway, synaptic transmission of auditory stimuli and synaptic plasticity of neutral and aversive learning and memory processes. However, the lack of selectivity of available pharmacological agents towards the most prominent LTCC isoforms in the brain, namely Caᵥ1.2 and Caᵥ1.3, has hampered the elucidation of the precise contribution made by each specific channel isoform within these specific physiological processes. Modern genetic approaches, both in rodents and in human, have recently enhanced our understanding of the selective functional roles of Caᵥ1.2 and Caᵥ1.3 channels. In rodents, the characterisation of global and conditional isoform-specific knockouts suggests a contribution of Caᵥ1.2 channels in spatial memory formation, whereas Caᵥ1.3 channels seem to be involved in the consolidation of fear memories and in neurodegenerative mechanisms associated with the development of Parkinson’s disease. With regard to the molecular mechanisms underlying drug addiction, Caᵥ1.3 channels are necessary for the development and Caᵥ1.2 channels for the expression of cocaine and amphetamine behavioural sensitisation. In humans, both the identification of naturally occurring LTCC variants (“channelopathies”) and unbiased genome-wide association studies have linked LTCCs to working memory performance in healthy individuals and schizophrenic patients. Individually, CACNA1C polymorphisms and CACNA1D variants have been linked to a variety of psychiatric diseases and to congenital deafness, respectively. However, the contribution of individual LTCCs and their polymorphisms to human brain function and diseases remains unclear, necessitating the use of isoform-specific pharmacological agents.