'New' functions for 'old' proteins: The role of the calcium-binding proteins calbindin D-28k, calretinin and parvalbumin, in cerebellar physiology. Studies with knockout mice

Abstract

Calretinin (CR), calbindin D-28k (CB) and parvalbumin (PV) belong to the large family of EF-hand calcium-binding proteins, which comprises more than 200 members in man. Structurally these proteins are characterized by the presence of a variable number of evolutionary well-conserved helix-loop-helix motives, which bind Ca2+ ions with high affinity. Functionally, they fall into two groups: by interaction with target proteins, calcium sensors translate calcium concentrations into signaling cascades, whereas calcium buffers are thought to modify the spatiotemporal aspects of calcium transients. Although CR, CB and PV are currently being considered calcium buffers, this may change as we learn more about their biology. Remarkable differences in their biophysical properties have led to the distinction of fast and slow buffers and suggested functional specificity of individual calcium buffers. Evaluation of the physiological roles of CR, CB and PV has been facilitated by the recent generation of mouse strains deficient in these proteins. Here, we review the biology of these calcium-binding proteins with distinct reference to the cerebellum, since they are particularly enriched in specific cerebellar neurons. CR is principally expressed in granule cells and their parallel fibres, while PV and CB are present throughout the axon, soma, dendrites and spines of Purkinje cells. PV is additionally found in a subpopulation of inhibitory interneurons, the stellate and basket cells. Studies on deficient mice together with in vitro work and their unique cell type-specific distribution in the cerebellum suggest that these calcium-binding proteins have evolved as functionally distinct, physiologically relevant modulators of intracellular calcium transients. Analysis of different brain regions suggests that these proteins are involved in regulating calcium pools critical for synaptic plasticity. Surprisingly, a major role of any of these three calcium-binding proteins as an endogenous neuroprotectant is not generally supported.

Differences in locomotor behavior revealed in mice deficient for the calcium-binding proteins parvalbumin, calbindin D-28k or both

“…Furthermore, these mice were normal and indistinguishable from the other littermates with respect to development, physical activity and behavior under standard housing conditions. Closer inspection of PV−/−, CB−/− and PV−/−CB−/− mice revealed significant functional alterations at cortical, hippocampal and cerebellar levels (for a review on the cerebellum, see [4]). Electrophysiological recordings of cortical, hippocampal and cerebellar sites in PV−/− mice showed important modifications in the function of the inhibitory systems [14,16,17,35].…”

“…They are implicated to contribute to the regulation of Ca 2+ homeostasis by acting as cytosolic Ca 2+ buffers [4][5][6] and recent experiments on CB suggest that this protein might have additional functions as a Ca 2+ sensor [7,8]. PV is almost exclusively expressed in inhibitory GABAergic interneurons in different regions including the neocortex, cerebellum, hippocampus and the reticular nucleus of the thalamus (RTN) of the mammalian brain and also in few projection neurons.…”

“…CBpositive cells include both, interneurons and projection neurons including pyramidal cells. Co-expression of PV and CB is rare and the only clearly defined neuron population expressing high levels of both CaBPs is the Purkinje cells of the cerebellum [4,9]. Additionally, PV is expressed in fast-contracting muscles [10].…”

Ectopic parvalbumin expression in mouse forebrain neurons increases excitotoxic injury provoked by ibotenic acid injection into the striatum

“…While initial investigations mainly reported on a correlation of preferentially surviving neuronal populations and specific Ca 2+ buffers, as discussed in D' Orlando et al (2001Orlando et al ( , 2002, more recent studies have directly addressed the question of neurodegeneration. Systems in vitro or in vivo, where expression levels of CaBPs were directly manipulated, include transfected cell lines or transgenic animals with either deletions of CaBP genes or ectopically expressing CaBPs (reviewed in Schwaller et al, 2002).…”

Circadian proteomics of the mouse retina

“…Spot 1966 contained calbindin D28 that buffers cytosolic Ca 21 [40]. In the retinal photoreceptor cells, it is well known that intracellular Ca 21 plays a central role in photoreceptor adaptation [41].…”