Emerging mechanisms and consequences of calcium regulation of alternative splicing in neurons and endocrine cells
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Cellular and Molecular Life Sciences
Review
Emerging mechanisms and consequences of calcium regulation of alternative splicing in neurons and endocrine cells Aleh Razanau · Jiuyong Xie
Received: 5 April 2013 / Revised: 21 May 2013 / Accepted: 27 May 2013 © Springer Basel 2013
Abstract Alternative splicing contributes greatly to proteomic complexity. How it is regulated by external stimuli to sculpt cellular properties, particularly the highly diverse and malleable neuronal properties, is an underdeveloped area of emerging interest. A number of recent studies in neurons and endocrine cells have begun to shed light on its regulation by calcium signals. Some mechanisms include changes in the trans-acting splicing factors by phosphorylation, protein level, alternative pre-mRNA splicing, and nucleocytoplasmic redistribution of proteins to alter protein–RNA or protein–protein interactions, as well as modulation of chromatin states. Importantly, functional analyses of the control of specific exons/splicing factors in the brain point to a crucial role of this regulation in synaptic maturation, maintenance, and transmission. Furthermore, its deregulation has been implicated in the pathogenesis of neurological disorders, particularly epilepsy/ seizure. Together, these studies have not only provided mechanistic insights into the regulation of alternative splicing by calcium signaling but also demonstrated its impact on neuron differentiation, function, and disease. This may also help our understanding of similar regulations in other types of cells.
A. Razanau · J. Xie (*) Department of Physiology, University of Manitoba, 439 BMSB, 745 Bannatyne Ave, Winnipeg R3E 0J9, Canada e-mail: [email protected] J. Xie Department of Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Keywords Alternative splicing mechanisms · Calcium signalling · Neuronal functions · Neurological disorders · Epilepsy/seizure
Introduction Alternative splicing through the selective exclusion or inclusion of pre-mRNA sequences is an important mechanism for the regulation of gene expression in metazoans. This in most cases leads to the generation of multiple protein isoforms from single genes, greatly expanding the coding capacity of the genome. In humans, about 95 % of protein-coding genes undergo alternative splicing, suggesting that it affects nearly every process in cells [1, 2]. The regulation is particularly prominent in neurons where tens of thousands of variant proteins could be produced from single genes for the highly diverse neuronal properties [3–6]. Not surprisingly, aberrant splicing accounts for up to 50 % of the defects caused by mutations that result in human diseases [7–9]. Precise recognition of splice sites and removal of RNA sequences (introns) are performed by the spliceosome, a multi-subunit molecular machine assembled stepwise on specific RNA sequence elements at the 5′ and 3′ splice sites [10]. In higher eukaryotes, these sites are highly degenerate, and are often
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