Calretinin: from a "simple" Ca(2+) buffer to a multifunctional protein implicated in many biological processes.

Beat Schwaller

doi:10.3389/fnana.2014.00003

Abstract

The hexa-EF-hand Ca2+-binding protein calretinin (CR) is predominantly expressed in specific neurons of the central and peripheral nervous system. However, CR expression is also observed in non-neuronal cells, e.g., during embryonic development and in mesothelioma cells. Of the 6 EF-hand domains, 5 are functional; the first 4 domains form 2 pairs showing high cooperativity within a pair that results in non-linear modulation of intracellular Ca2+ signals by CR. EF-hand domain 5 has a low affinity and represents the identified interaction site with CR-binding partners present in mouse cerebellar granule cells. CR binding to other targets including the pore-forming α1 subunit of the Ca2+ channel CaV2.1, as well as to huntingtin indicates additional Ca2+ sensor functions besides the well-known Ca2+-buffering functions. The absence of CR in cerebellar granule cells of CR−/− mice results in increased excitability and altered firing of Purkinje cells and promotes cerebellar 160-Hz oscillations impairing motor coordination. The putative role of CR in neuroprotection is still highly discussed. Altogether, CR emerges as a multi-functional protein also associated with development, i.e., cell proliferation, differentiation, and cell death.

Highlights

The hexa-EF-hand Ca2+-binding protein calretinin (CR) is predominantly expressed in specific neurons of the central and peripheral nervous system
Each domain consists of an alpha-helix of approximately 10 amino acids, a Ca2+-chelating loop of 12 amino acids and a second alpha-helix that is oriented perpendicular to the first one (for more details on the EF-hand structure, see (Schwaller, 2010)
CR (Mr 31 kDa) initially discovered in the retina, the name: calcium + retina = CR consists of 271 amino acids in many species and is highly conserved; the number of amino acids varies from 269 (e.g., Gallus gallus; Chicken) to 273 (e.g., Monodelphis domestica; Gray short-tailed opossum)

Summary

Introduction

The hexa-EF-hand Ca2+-binding protein calretinin (CR) is predominantly expressed in specific neurons of the central and peripheral nervous system. If the same increase occurs at elevated [Ca2+]i, in the order of 1 μM, when the first site of a pair is in the Ca2+-bound form, cooperativity sets in and CR functions almost like the fast buffer BAPTA (for more details on this behavior, e.g., on the spatiotemporal patterns of IP3-evoked Ca2+ signals, see Dargan et al (2004) or on CR’s role modeled for a train of intracellular Ca2+ signals, see Figure 3 in (Schwaller, 2009).

Results

Conclusion