Evolution and functional diversity of the Calcium Binding Proteins (CaBPs)

Abstract

The mammalian central nervous system (CNS) exhibits a remarkable ability to process, store, and transfer information. Key to these activities is the use of highly regulated and unique patterns of calcium signals encoded by calcium channels and decoded by families of specific calcium-sensing proteins. The largest family of eukaryotic calcium sensors is those related to the small EF-hand containing protein calmodulin (CaM). In order to maximize the usefulness of calcium as a signaling species and to permit the evolution and fine tuning of the mammalian CNS, families of related proteins have arisen that exhibit characteristic calcium binding properties and tissue-, cellular-, and sub-cellular distribution profiles. The Calcium Binding Proteins (CaBPs) represent one such family of vertebrate specific CaM like proteins that have emerged in recent years as important regulators of essential neuronal target proteins. Bioinformatic analyses indicate that the CaBPs consist of two subfamilies and that the ancestral members of these are CaBP1 and CaBP8. The CaBPs have distinct intracellular localizations based on different targeting mechanisms including a novel type-II transmembrane domain in CaBPs 7 and 8 (otherwise known as calneuron II and calneuron I, respectively). Recent work has led to the identification of new target interactions and possible functions for the CaBPs suggesting that they have multiple physiological roles with relevance for the normal functioning of the CNS.

CaBP1, a neuronal Ca 2 + sensor protein, inhibits inositol trisphosphate receptors by clamping intersubunit interactions

“…EF3 and EF4 in the C lobe of CaBP1 exhibit canonical Ca 2+ -induced conformational changes (18,19). Many splice variants and isoforms of CaBPs are expressed in different neurons (20)(21)(22), and their targets include a variety of ion channels (2). CaBP1, for example, regulates voltage-gated P/Q-type (23) and L-type Ca 2+ channels (24) and a transient receptor potential channel, TRPC5 (25).…”

“…There is, however, evidence, that proteins with EF-hand Ca 2+ -binding motifs can regulate gating of InsP 3 Rs. These include calmodulin (CaM) (10)(11)(12), calmyrin (CIB1) (13), and neuronal Ca 2+ sensor (NCS) proteins (2). The latter comprise a branch of the CaM superfamily that includes NCS-1 (14) and Ca 2+ -binding protein 1 (CaBP1) (15,16).…”

“…The latter comprise a branch of the CaM superfamily that includes NCS-1 (14) and Ca 2+ -binding protein 1 (CaBP1) (15,16). CaBP1-5 proteins (2,17) have four EF hands that form pairs within the N lobe (EF1 and 2) and C lobe (EF3 and 4). The two lobes are structurally independent (18) and connected by a flexible linker (18).…”

“…] c ) regulate many cellular events, including acute and long-term changes in neuronal activity (1)(2)(3). Release of Ca 2+ from intracellular stores is controlled by intracellular Ca 2+ channels (4), the most common of which are inositol 1,4,5-trisphosphate receptors (InsP 3 Rs) (5,6).…”

Expression of CaBP transcripts in retinal bipolar cells of developing and adult zebrafish

“…The largest group of Ca 2+ -binding proteins are structurally conserved EF-hand containing proteins belonging to the calmodulin superfamily. Within this superfamily, the vertebrate-specific CaBP subfamily comprises CaBP1, CaBP2, CaBP4 and CaBP5 in mammals [2] [3] [4]. In zebrafish, the CaBP subfamily is expanded to 8 members encoded by cabp1a, cabp1b, cabp2a, cabp2b, cabp4a, cabp4b, cabp5a and cabp5b [5], most likely due to duplicate gene retention after teleost-specific whole genome duplication [6].…”