Upregulated expression of oncomodulin, the beta isoform of parvalbumin, in perikarya and axons in the diencephalon of parvalbumin knockout mice

Abstract

Abstract-The calcium-binding proteins parvalbumin, calbindin D-28k, calretinin and calcineurin are present in subsets of GABAergic gigantic calyciform presynaptic terminals of the reticular thalamic nucleus (RTN). Previously it was hypothesized that GABA and calcium-binding proteins including parvalbumin are not only colocalized in the same neuron subpopulation, but that GABA synthesis and parvalbumin expression could be also genetically regulated by a common mechanism. Moreover, parvalbumin expression levels could influence GABA synthesis. For this, we analyzed GABA immunoreactivity in RTN gigantic calyciform presynaptic terminals of parvalbumin-deficient (PV؊/؊) mice. With respect to GABA immunoreactivity we found no differences compared to wild-type animals. However, using a polyclonal parvalbumin antibody raised against full-length rat muscle parvalbumin on brain sections of PV؊/؊ mice, we observed paradoxical parvalbumin immunoreactivity in partly varicose axons in the diencephalon, mainly in the lamina medullaris externa surrounding the thalamus. A detailed immunohistochemical, biochemical and molecular biological analysis revealed this immunoreactivity to be the result of an upregulation of oncomodulin (OM), the mammalian beta isoform of parvalbumin in PV؊/؊ mice. In addition, OM was present in a sparse subpopulation of neurons in the thalamus and in the dentate gyrus. OM expression has not been observed before in neurons of the mammalian brain; its expression was restricted to outer hair cells in the organ of Corti. Our results indicate that the absence of parvalbumin has no major effect on the GABA-synthesizing system in RTN presynaptic terminals excluding a direct effect of parvalbumin on this regulation. However, a likely homeostatic mechanism is induced resulting in the upregulation of OM in selected axons and neuronal perikarya. Our results warrant further detailed investigations on the putative role of OM in the brain.

Cytosolic Ca2+ Buffers

“…An extracellular role for OM in retinal ganglion cell regeneration (Yin et al 2006) was reported, but see also Hauk et al (2008) and Schwaller (2009). An up-regulation of OM occurs in PV 2/2 mice in a sparse subpopulation of neurons in the thalamus and in the dentate gyrus, as well as in partly varicose axons in the diencephalon (Csillik et al 2010). The functional significance of ectopic OM expression and the exact identity of neurons expressing OM in PV 2/2 mice remain to be shown.…”

The renaissance of Ca2+-binding proteins in the nervous system: secretagogin takes center stage

“… 9 Oncomodulin has only been detected in the nervous system of mice lacking α-parvalbumin expression [50]. …”

“…Although most neurons express a typifying cytosolic Ca 2+ buffer protein in the brain, CBPs can occasionally co-localize [32,48,49]. Nevertheless, neurons appear to commit to certain Ca 2+ buffers since genetic removal of a CBP is usually not compensated by up-regulation of expression of another EF-hand CBP superfamily member (see however, [50]).…”

Engineering parvalbumin for the heart: optimizing the Mg2+ binding properties of rat β-parvalbumin

“…The PVs from both mammalian and fish skeletal muscle have relatively similar cation binding properties, especially with regard to possessing slow rates of Ca 2+ dissociation (White, 1988; Eberhard and Erne, 1994; Lee et al, 2000; Erickson and Moerland, 2006). On the other hand, mammalian β-PV, which is found in the brain, ear, placenta, and macrophages [not normally found in muscle (Belkacemi et al, 2002; Yin et al, 2006; Csillik et al, 2010)] has drastically lower affinity for both Ca 2+ and Mg 2+ compared to mammalian α-PV (Hapak et al, 1989). The rates of Ca 2+ and Mg 2+ exchange from mammalian β-PV are currently unknown and will be addressed in this manuscript.…”