The diversity of calcium sensor proteins in the regulation of neuronal function

Abstract

Calcium signaling in neurons as in other cell types mediates changes in gene expression, cell growth, development, survival, and cell death. However, neuronal Ca(2+) signaling processes have become adapted to modulate the function of other important pathways including axon outgrowth and changes in synaptic strength. Ca(2+) plays a key role as the trigger for fast neurotransmitter release. The ubiquitous Ca(2+) sensor calmodulin is involved in various aspects of neuronal regulation. The mechanisms by which changes in intracellular Ca(2+) concentration in neurons can bring about such diverse responses has, however, become a topic of widespread interest that has recently focused on the roles of specialized neuronal Ca(2+) sensors. In this article, we summarize synaptotagmins in neurotransmitter release, the neuronal roles of calmodulin, and the functional significance of the NCS and the CaBP/calneuron protein families of neuronal Ca(2+) sensors.

Figure 1.

Structures of the C2A and C2B domains of synaptotagmin I. 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 PDB files 1BYN and 1K5W, respectively.

Figure 2.

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 (PDB 1CLL) or in a complex with the IQ-like domain of the Ca_v1.2 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 3.

An interaction map showing protein–protein interactions made by some NCS proteins and CaBP1 compared to calmodulin. Known protein interactions for CABP1, hippocalcin, NCS-1, neurocalcin δ,VILIP1, and VILIP2. Links indicate where these target proteins have also been found to interact with calmodulin. It is also indicated whether these interactions require the Ca²⁺-bound form of the protein or not.

Figure 4.

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 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 N-terminus, which give rise to long and short isoforms (shown in orange). Calneurons 1 and 2 possess a 38 amino acid extension at their C-terminus (shown in purple).