Progesterone modulates inositol 1,4,5–trisphosphate–mediated calcium signaling in rod bipolar cells

Abstract

Abstract: : Purpose: The function of nerve cells is critically determined by the regulation of their cytosolic calcium concentration. Inositol–1,4,5–trisphosphate receptors (IP₃Rs), ligand–gated calcium channels on intracellular membranes, can modulate neuronal function substantially by releasing calcium from intracellular stores. Endogenous steroid hormones, their metabolic products, and chemical derivatives mediate protection against cellular damage in a variety of organs and cell types, preventing the consequences of acute insults and degenerative diseases that ultimately lead to cell death. Thus, evaluating the function of steroid hormones in the retina could not only reveal novel therapeutic strategies for treating retinal degeneration, but may represent an ideal system to study mechanism of disease progression and develop relevant treatments for neurodegenerative diseases. Here, we analyzed the effect of progesterone (P4) on IP₃Rs expressed by mammalian rod bipolar cells, the first interneurons of the retina. Methods: The expression and distribution of IP₃Rs and progesterone receptors (PRs) in rod bipolar cells from rat and mouse retinas was analyzed using immunocytochemistry and specific antibodies. Functional effects were determined with single channel electrophysiology of IP₃Rs and optical imaging of intracellular Ca²⁺ concentrations. Results: IP₃Rs and PRs were co–expressed and co–distributed in the somata of rod bipolar cells. Treatment of rod bipolar cells with P4 induced phosphorylation of IP₃Rs, which was accompanied by an increase in IP₃R channel activity and prolonged transients of elevated cytosolic Ca²⁺ concentrations. The kinetics of intracellular Ca²⁺ signals were spatio–temporally correlated with the kinetics of IP₃R phosphorylation and the distribution of IP₃Rs. Conclusion: Our data indicate that steroid hormones can functionally influence the activity of intracellular Ca²⁺ release channels and thereby influence functional properties of neurons expressing such channels. Steroid hormones can induce intracellular Ca²⁺ transients directly without the involvement of other messenger substances. At the same time, steroid hormone activity can alter also the properties of neurons and influence subsequent responses to external stimuli. Supported by a German National Merit Scholarship Foundation scholarship (CM), and a grant from The UNT Health Science Center Intramural Research Program (PK, MS).

Keywords: bipolar cells • calcium • phosphorylation