Neuronal calcium sensor proteins: generating diversity in neuronal Ca2+ signalling

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Abstract
Many aspects of neuronal function are regulated by changes in the concentration of intracellular free Ca2+. To fully understand how this occurs, an appreciation is needed of how changes in the concentration of a simple ion can modify neuronal function in various ways, and how the same ion can produce distinct outcomes in the same type of neuron. The diversity of events controlled by Ca2+ are partly a consequence of distinct types of Ca2+ signal that differ spatially, temporally and in magnitude. The differing outcomes are due to the actions of various Ca2+ sensor proteins that transduce the Ca2+ signals into specific changes in cellular function. A number of Ca2+-binding proteins related to calmodulin are enriched in or expressed only in the nervous system, where they have distinct roles in the regulation of neuronal function. These include the neuronal calcium sensor (NCS) protein family, members of which have been implicated in a wide range of Ca2+ signalling events. During evolution there has been a progressive increase in the size of the NCS family. Mammals have a highly conserved set of 14 NCS genes that encode NCS-1, three visinin-like proteins (VILIPs), hippocalcin, neurocalcin-δ, recoverin, three guanylyl cyclase-activating proteins (GCAPs) and four voltage-gated potassium (Kv) channel-interacting proteins (KchIPs). There are also several alternatively spliced versions of the KChIPs. NCS proteins are in a Ca2+-free state under resting conditions and all have a high affinity for Ca2+, which allows them to bind Ca2+ following small increases in concentration above resting levels. Some NCS proteins are cytosolic at resting Ca2+and reversibly associate with membranes, but others such as NCS-1 and GCAPs are always associated with membranes. Members of the NCS family have distinct target proteins that they regulate. Many of these do not overlap with calmodulin and so contribute to the specificity of the NCS protein function. The NCS proteins regulate many cellular events in neurons and in retinal photoreceptors. Evidence for these functions originally came from biochemical analyses and studies of the effects of overexpressing the proteins, but in recent years many of these proposed functions have been confirmed in genetic studies. Changes in expression levels of certain NCS proteins in disease states, and initial analyses of single nucleotide polymorphisms in the Ncs-1 gene, have indicated possible links to neurological disorders. NCS-1 is most probably derived from the primordial NCS precursor; it is expressed from yeast to man and has multiple functions due to its ability to interact with and regulate many target proteins. By contrast, some NCS proteins have specific, single functions; recoverin inhibits rhodopsin kinase and the GCAPs regulate guanylyl cyclases in the retina. The KChIPs are a large subfamily with distinct properties, subcellular localization and cell type expression patterns. They are required for the normal traffic and gating properties of Kv4 channels, are involved in the repression of specific gene transcription and interact with presenilin. Genetic studies have demonstrated that individual NCS proteins have essential functions that cannot be compensated for by other Ca2+ sensors. Differences in Ca2+ affinity, localization, different cellular dynamics, differential cellular expression and distinct target proteins are factors in the specialization of NCS protein function.

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