Visinin-like proteins (VSNLs): interaction partners and emerging functions in signal transduction of a subfamily of neuronal Ca2+-sensor proteins

Abstract

The visinin-like protein (VSNL) subfamily, including the founder protein VILIP-1, VILIP-2, VILIP-3, hippocalcin and neurocalcin δ, constitute a highly homologous subfamily of neuronal calcium sensor (NCS) proteins. Comparative studies have shown that VSNLs are expressed predominantly in the brain with restricted expression patterns in different subsets of neurons, but are also found in peripheral organs. In addition, the proteins display differences in their calcium affinities, their membrane binding kinetics and in the intracellular targets to which they associate after calcium binding. Even though the proteins use a similar calcium-myristoyl switch mechanism to translocate to cellular membranes, they show calcium-dependent localization to different subcellular compartments when expressed in the same neuron. These distinct calcium-myristoyl switch properties might be explained by specificity for defined phospholipids and membrane-bound targets, which enable VSNLs to modulate various cellular signal transduction pathways, including cyclic nucleotide and MAPK signaling. An emerging theme is the direct or indirect effect of VSNLs on gene expression and the interaction with components of membrane trafficking complexes which may determine a role in membrane trafficking of different receptors and ion channels, such as glutamate receptors of the kainate and AMPA subtype, nicotinic ACh receptors and Ca2+-channels. One hypothesis is that the highly homologous VSNLs have evolved to fulfill specialized functions in membrane trafficking and thereby affect neuronal signaling and differentiation in defined subsets of neurons. VSNLs are involved in differentiation processes showing a tumor invasion suppressor function in peripheral organs. Finally, VSNLs play neuroprotective and neurotoxic roles and have been implicated in neurodegenerative diseases.

Protein Profile and Morphological Alterations in Penumbra after Focal Photothrombotic Infarction in the Rat Cerebral Cortex

“…It influences different signaling cascades including cyclic nucleotide and MAPK signaling through a Ca 2+ / myristoyl switch mechanism. After [Ca 2+ ] i increase, VILIP1 moves to the cellular membranes and regulates vesicular trafficking and recycling of receptors and ion channels [46]. Upon stroke, it is released from damaged neuronal cells into the cerebrospinal fluid and blood serum being a stroke marker [47].…”

Neuronal Calcium Sensor-1 (Ncs1p) Is Up-regulated by Calcineurin to Promote Ca2+ Tolerance in Fission Yeast

“…Thus, Ca 2ϩ -induced expression of Ncs1p, Pmr1p, and Pmc1p should generate similar levels of all three proteins, making it possible for Ncs1p to bind and serve as a regulatory subunit for each pump or perhaps assist in the trafficking of these pumps to cell membranes. Indeed, NCS proteins have been shown to facilitate Ca 2ϩ -induced trafficking of ion channels and other membrane proteins (74,75). Ca 2ϩ -induced activation of Ca 2ϩ pumps could maximize Ca 2ϩ efflux under extreme external conditions and thereby help maintain a viable cytosolic Ca 2ϩ concentration.…”

Promoter Regulation of the Visinin-like Subfamily of Neuronal Calcium Sensor Proteins by Nuclear Respiratory Factor-1

“…3 (visinin-like protein-1, gene name VSNL1) is a member of the visinin-like subfamily of neuronal Ca 2ϩ sensor (NCS) proteins, which include neurocalcin-␦ (NCALD), hippocalcin (HPCA), VILIP-1, VILIP-2 (HPCAL4), and VILIP-3 (HPCAL1) (1)(2)(3). In the nervous system, VILIP-1 was consistently found to be expressed in hippocampal neurons, cerebellar granular cells, interneurons, cortical pyramidal cells, as well as in other neurons (4,5).…”