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J. Biol. Chem., Vol. 281, Issue 45, 34086-34095, November 10, 2006

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Ryanodine Receptors in Liver^*

From the Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103

The ryanodine receptor has been mainly regarded as the Ca²⁺ release channel from sarcoplasmic reticulum controlling skeletal and cardiac muscle contraction. However, many studies have shown that it is widely expressed, with functions not restricted to muscular contraction. This study examined whether ryanodine receptor plays a role in calcium signaling in the liver. RT-PCR analysis of isolated hepatocytes showed expression of a truncated type 1 ryanodine receptor, but no type 2 or type 3 message was detected. We also detected binding sites for [³H]ryanodine in the microsomal cellular fraction and in permeabilized hepatocytes. This binding was displaced by caffeine and dantrolene, but not by ruthenium red, heparin or cyclic ADP-Ribose. Ryanodine, by itself, did not trigger Ca²⁺ oscillations in either primary cultured hepatocytes or hepatocytes within the intact perfused rat liver. In both preparations, however, ryanodine significantly increased the frequency of the cytosolic free [Ca²⁺] oscillations evoked by an ₁ adrenergic receptor agonist. Experiments in permeabilized hepatocytes showed that both ryanodine and cyclic ADP-ribose evoked a slow Ca²⁺ leak from intracellular stores and were able to increase the Ca²⁺-released response to a subthreshold dose of inositol 1,4,5-trisphosphate. Our findings suggest the presence of a novel truncated form of the type 1 ryanodine receptor in rat hepatocytes. Ryanodine modulates the pattern of cytosolic free [Ca²⁺] oscillations by increasing oscillation frequency. We propose that the Ca²⁺ released from ryanodine receptors on the endoplasmic reticulum provides an increased pool of Ca²⁺ for positive feedback on inositol 1,4,5-trisphosphate receptors.

Received for publication, August 15, 2006

^* This work was supported by Grants DK38422 and AA014980 from the National Institutes of Health and the Thomas P. Infusino Endowment (to A. P. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology and Physiology, UMDNJ, 185 South Orange Ave., Newark, NJ 07103-2714. Tel.: 973-972-4460; Fax: 973-972-7950; E-mail: thomasap{at}umdnj.edu.

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