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Review
. 2019 May 1;11(5):a035154.
doi: 10.1101/cshperspect.a035154.

Calcium Sensors in Neuronal Function and Dysfunction

Robert D Burgoyne  1 , Nordine Helassa  1 , Hannah V McCue  2 , Lee P Haynes  1
Affiliations
Review

Calcium Sensors in Neuronal Function and Dysfunction

Robert D Burgoyne et al. Cold Spring Harb Perspect Biol. .

Abstract

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 addition 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.

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Figures

Figure 1.
Figure 1.
Structures of the C2A and C2B domains of synaptotagmin 1. The structures show the isolated C2 domains in their Ca2+-loaded state with the bound Ca2+ ions shown in green. The coordinates for the structures for the C2A and C2B domains come from the Protein Data Bank (PDB) files 1BYN and 1K5W, respectively.
Figure 2.
Figure 2.
Potential role of synaptotagmin 1 in synaptic vesicle exocytosis. Key components of the minimal fusion machinery are associated with the synaptic vesicle and the plasma membrane (1). Neurotransmitter release is triggered by Ca entry though voltage-gated calcium channels. Ca2+ binds to synaptotagmin 1, which may then lead to vesicle docking via interaction with phospholipids or with SNAP-25 on the plasma membrane (2). The SNARE complex assembles from the key components of VAMP, SNAP-25, and syntax and synaptotagmin associates with the complex (3). Through as-yet undefined steps synaptotagmin become dissociated from the SNARE complex and fusion of the vesicle with the plasma membrane occurs to allow release of neurotransmitter from the vesicle (4).
Figure 3.
Figure 3.
Comparison of the structures of Ca2+-loaded calmodulin and yeast frequenin with and without bound target peptides. The structures at the top are of Ca2+-bound calmodulin alone (Protein Data Base [PDB] 1CLL) or in a complex with the IQ-like domain of the CaV1.2 Ca2+-channel α-subunit (PDB 2F3Z). The structures at the bottom are of the Ca2+-bound yeast frequenin (Frq1) alone (PDB 1FPW) or in a complex with the binding domain from Pik1 (PDB 2JU0). In each of the complexes the target peptide is shown in yellow.
Figure 4.
Figure 4.
Schematic illustration of the pore-forming a1 subunit of a CaV1.2 channel. The a1 subunit is composed of four domains (I–IV), each consisting of six putative transmembrane segments (orange). Several potential binding sites for Ca2+ sensors (yellow) have been identified in the amino-terminal (NT) and the carboxy-terminal region (A, C, and IQ) of CaV1.2 channels. Calmodulin (green), one of the major Ca2+ sensors, has been shown to be preassociated with the channel through its interaction with the IQ motif. Once calmodulin becomes Ca2+-loaded, it exerts its effects on channel function through either its amino or its carboxy lobe.
Figure 5.
Figure 5.
Major known target proteins for neuronal calcium sensor (NCS)-1 indicating interactions that require either the Ca2+-bound or the apo form of NCS-1. The interactions shown include ones that are based on in vitro binding assays as well as interactions that have been substantiated and shown to have physiological relevance in functional studies.
Figure 6.
Figure 6.
Comparison of the mode of binding of target peptides to neuronal calcium sensor (NCS)-1. Cartoon representation of the structures of (A) NCS-1 in complex with two molecules of D2R peptide (magenta and cyan) (PDB 5AER), (B) ScNcs1in complex with fragment of Pik1 (yellow) (2JU0) (45), (C) NCS-1 in complex with one molecule of GRK1 peptide (pink) (PDB 5AFP), (D) KChIP1 with a fragment of bound Kv4.3 (blue) (PDB 2I2R) (50), (E) recoverin bound to the amino terminus of GRK1 residues 1–25 with GRK1 peptide (red; PDB 2I94) (52), and (F) overlay of structures 5AER and 5AFP showing the locations of the D2R bound in the amino site and GRK1 peptides. The peptide orientations are indicated as N and C in italics and the orientations of the NCS protein are identical in all the structures. The EF3/EF4 linker is colored brown and the carboxy-terminal region green; for clarity, these regions are indicated only for the NCS-1-D2R peptide complex. In all the structures, Ca ions are shown as brown spheres. (From Pandalaneni et al. 2015; adapted, with permission, from the authors.)
Figure 7.
Figure 7.
Effect of dystonia mutations on the structure of hippocalcin and its effect on calcium entry. (Top) Alignment of hippocalcin crystal structure (magenta) with hippocalcin (T71N) (marine) and hippocalcin (A190T) (salmon) did not show any significant difference. Crystal structures were obtained for wild-type (wt) human hippocalcin (PDB 5G4P), hippocalcin (T71N) (PDB 5M6C), and hippocalcin (A190T) (PDB 5G58) at a resolution of the 2.42, 3.00, and 2.54 Å, respectively (Helassa et al. 2017). (Bottom) Dystonia-causing hippocalcin mutants increase depolarization-induced calcium influx. Differentiated SH-SY5Y cells transfected with hippocalcin-mCherry constructs were loaded with Fluo-4 to monitor calcium concentration changes. After KCl depolarization, live cells were imaged on a spinning-disk confocal microscope. Maximum intracellular calcium increase and time course after KCl stimulation, showing that both hippocalcin (T71N) and hippocalcin (A190T) increased calcium entry in response to depolarization. (From Helassa et al. 2017; adapted under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium.)
Figure 8.
Figure 8.
Schematic diagram showing the domain structure of calmodulin and members of the CaBP/calneuron protein family. Active EF-hand motifs are shown in red and inactive EF-hand motifs are shown in pink. Compared to calmodulin the calcium-binding proteins (CaBPs) have an extended linker region between their first EF-hand pair and their second EF-hand pair (shown in black). CaBP1 and CaBP2 have an N-myristoylation site (shown in blue). CaBP1 and CaBP2 have alternative splice sites at their amino terminus, which give rise to long and short isoforms (shown in orange). Calneurons 1 and 2 possess a 38 amino acid extension at their carboxyl terminus (shown in purple).
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