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Calcium Sensors in Neuronal Function and Dysfunction Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Calcium Sensors in Neuronal Function and Dysfunction Robert D. Burgoyne,1 Nordine Helassa,1 Hannah V. McCue,2 and Lee P. Haynes1 1Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom 2Centre for Genomic Research, University of Liverpool, Liverpool, United Kingdom Correspondence: [email protected] Calcium signaling in neurons as in other cell types can lead to varied changes in cellular function. Neuronal Ca2+ signaling processes have also become adapted to modulate the function of specific pathways over a wide variety of time domains and these can have effects on, for example, axon outgrowth, neuronal survival, and changes in synaptic strength. Ca2+ also plays a key role in synapses as the trigger for fast neurotransmitter release. Given its physiological importance, abnormalities in neuronal Ca2+ signaling potentially underlie many different neurological and neurodegenerative diseases. The mechanisms by which changes in intracellular Ca2+ concentration in neurons can bring about diverse responses is underpinned by the roles of ubiquitous or specialized neuronal Ca2+ sensors. It has been established that synaptotagmins have key functions in neurotransmitter release, and, in ad- dition to calmodulin, other families of EF-hand-containing neuronal Ca2+ sensors, including the neuronal calcium sensor (NCS) and the calcium-binding protein (CaBP) families, play important physiological roles in neuronal Ca2+ signaling. It has become increasingly apparent that these various Ca2+ sensors may also be crucial for aspects of neuronal dysfunction and disease either indirectly or directly as a direct consequence of genetic variation or mutations. An understanding of the molecular basis for the regulation of the targets of the Ca2+ sensors and the physiological roles of each protein in identified neurons may contribute to future approaches to the development of treatments for a variety of human neuronal disorders. alcium signaling in many cell types can me- Changes in the concentration of intracellular C 2+ 2+ diate a diverse range of changes in cellular free Ca ([Ca ]i) are essential for the transmis- function affecting gene expression, cell growth, sion of information through the nervous system development, survival, and cell death. In addi- as the trigger for neurotransmitter release at syn- 2+ tion, neuronal calcium signaling processes have apses. In addition, alterations in [Ca ]i can lead become adapted to modulate the function of to a wide variety of different physiological other important pathways in the brain, including changes that can modify neuronal functions neuronal survival, axon outgrowth (Spitzer over a range of time domains of milliseconds 2006), and changes in synaptic strength (Cat- through 10 sec, to minutes to days or longer terall and Few 2008; Catterall et al. 2013). (Berridge 1998). It has long been believed that Editors: Geert Bultynck, Martin D. Bootman, Michael J. Berridge, and Grace E. Stutzmann Additional Perspectives on Calcium Signaling available at www.cshperspectives.org Copyright © 2019 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a035154 1 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press R.D. Burgoyne et al. the physiological outcome from a change in are the synaptotagmins that control neurotrans- 2+ [Ca ]i depends on its location, amplitude, and mitter release (Fernández-Chacón et al. 2001; duration. The importance of location becomes Südhof 2013), the ubiquitous EF-hand-contain- even more pronounced in neurons because of ing sensor calmodulin (Faas et al. 2011) that has their complex morphologies. Pathological many neuronal roles, and the more specific neu- changes in Ca2+ signaling pathways have been ronal EF-hand-containing proteins, including suggested to underlie various neuropathological the neuronal calcium sensor (NCS) proteins disorders (Braunewell 2005; Berridge 2010, (Burgoyne and Weiss 2001; Burgoyne 2007; Bur- 2018; Brini et al. 2014, 2017), including neuro- goyne and Haynes 2012, 2015) and the calci- logical abnormalities and neurodegenerative um-binding protein (CaBP)/calneuron families disorders (Popugaeva and Bezprozvanny 2013; (Haeseleer et al. 2002; Mikhaylova et al. 2006, Egorova and Bezprozvanny 2018; Pchitskaya 2011; McCue et al. 2010a; Haynes et al. 2012). et al. 2018; Secondo et al. 2018; Wegierski and The potential involvement of members of these Kuznicki 2018). Such changes have implicated protein families in neuronal disorders studied in Ca2+ entry pathways and the release of Ca2+ from both experimental models and in human sub- intracellular stores (Popugaeva and Bezproz- jects has become apparent in recent years. In vanny 2013; Schampel and Kuerten 2017; Ego- this review, we assess the information available rova and Bezprozvanny 2018; Secondo et al. on the physiological roles of these various Ca2+ 2018; Wegierski and Kuznicki 2018). sensors and their modes of action, and also how The nature, magnitude, and location of the they may contribute to neuronal dysfunction or Ca2+ signal is crucial for the particular effect of be involved in disease-related processes in the neuronal physiology (Burgoyne 2007). Highly nervous system. localized Ca2+ elevations because of Ca2+ entry though voltage-gated Ca2+ channels (VGCCs) lead to synaptic vesicle fusion with the pre- SYNAPTOTAGMINS synaptic membrane for neurotransmitter release The Physiology and Function within less than a millisecond (Burgoyne and of Synaptotagmins Morgan 1998; Barclay et al. 2005). Differently localized and timed Ca2+ signals can result in The synaptotagmins are transmembrane pro- changes to the properties of the VGCCs them- teins predominantly associated with synaptic selves (Catterall and Few 2008), to alterations in and secretory vesicles. There are multiple known synaptic plasticity (Catterall et al. 2013), or lead isoforms of synaptotagmins (Craxton 2004), of to changes in gene expression (Bito et al. 1997). which synaptotagmin 1 has been most widely Postsynaptic Ca2+ signals arising from activation studied. The role of synaptotagmins in neuro- of N-methyl-D-aspartate receptors (NMDARs) transmitter release has been the subject of in- give rise to two important processes in synaptic tense investigations, which have been extensively plasticity, long-term potentiation (LTP) and reviewed (Chapman 2008; Rizo and Rosenmund long-term depression (LTD). Interestingly, the 2008; Südhof and Rothman 2009). Synaptotag- 2+ 2+ fi Ca signals that bring about either LTP or LTD mins bind Ca with relatively low af nity (Kd > differ only in their amplitude and duration 10 µM) through their two C2 domains (C2A and (Yang et al. 1999). C2B) (Shao et al. 1998; Fernandez et al. 2001), Specific neuronal Ca2+ signals are likely to which are functional in many but not all syn- be decoded by various Ca2+ sensor proteins aptotagmin isoforms. Ca2+ binding by C2 do- (McCue et al. 2010b). These are proteins that mains requires coordination of Ca2+ by both undergo a conformational change on Ca2+ bind- the protein and membrane lipids, and this lipid ing allowing them to interact with and regulate interaction is a key aspect for its function. In various target proteins (Ikuro and Ames 2006; synaptotagmin 1, the C2A and C2B domains Burgoyne and Haynes 2015). Among the Ca2+ (Fig. 1) bind three and two Ca2+ ions, respective- sensors that are important for neuronal function ly (Shao et al. 1998; Fernandez et al. 2001). It is 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a035154 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Neuronal Calcium Sensor Proteins C2A C2B brevin. In the case of neurotransmitter release, vesicle fusion is tightly regulated and requires a Ca2+ signal for activation. Ca2+ entry through VGCCs leading to Ca2+ elevation in local micro- domains close to the mouth of the Ca2+ channels is able to trigger rapid (<1 msec) fusion of syn- aptic vesicles. A synaptotagmin can bind to both syntaxin and SNAP-25, and fast neurotransmit- ter release requires synaptotagmin (Geppert et al. 1994), probably prebound to assembled or partially assembled SNARE complexes (Schiavo et al. 1997; Rickman et al. 2006), so that Ca2+-in- duced interaction with phospholipids can occur rapidly (Xue et al. 2008). It is still under debate how important synaptotagmin is in vesicle dock- Figure 1. Structures of the C2A and C2B domains of ing (de Wit et al. 2009; Chang et al. 2018) and synaptotagmin 1. The structures show the isolated C2 how it acts at the plasma membrane in fusion domains in their Ca2+-loaded state with the bound itself (Fig. 2; Tang et al. 2006; Hui et al. 2009). Ca2+ ions shown in green. The coordinates for the A synaptotagmin could act as a brake on fusion 2+ structures for the C2A and C2B domains come that is relieved by Ca binding or have a positive fi from the Protein Data Bank (PDB) les 1BYN and role in membrane fusion (Chicka et al. 2008). A 1K5W, respectively. recent focus has been on the combined role of synaptotagmin and another SNARE-interacting now well established that synaptotagmin 1 is the protein, complexin, in timing synaptic vesicle key sensor for evoked, synchronous neurotrans- fusion (Südhof and Rothman 2009). The struc- mitter release in many classes of neurons (Fer- ture of a complex of synaptotagmin 1, com- nández-Chacón et al. 2001). More recently, a key plexin, and the SNAREs has been characterized role for synaptotagmin 7 in neurotransmission (Zhou et al. 2017). It was suggested that this tri- has also been identified (Turecek and Regehr partite complex could be a primed structure at 2018) and synaptotagmin 2 has been shown to the site of vesicle docking that would then need be a Ca2+ sensor in central inhibitory neurons to be disrupted to allow fusion to occur.
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