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J. Biol. Chem., Vol. 282, Issue 32, 23096-23103, August 10, 2007

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Targeting and Retention of Type 1 Ryanodine Receptors to the Endoplasmic Reticulum^*

From the Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom

Most ryanodine receptors and their relatives, inositol 1,4,5-trisphosphate receptors, are expressed in the sarcoplasmic or endoplasmic reticulum (ER), where they mediate Ca²⁺ release. We expressed fragments of ryanodine receptor type 1 (RyR1) in COS cells alone or fused to intercellular adhesion molecule-1 (ICAM-1), each tagged with yellow fluorescent protein, and used confocal imaging and glycoprotein analysis to identify the determinants of ER targeting and retention. Single transmembrane domains (TMD) of RyR1 taken from the first (TMD1–TMD2) or last (TMD5–TMD6) pair were expressed in the ER membrane. TMD3–TMD4 was expressed in the outer mitochondrial membrane. The TMD outer pairs (TMD1–TMD2 and TMD5–TMD6) retained ICAM-1, a plasma membrane-targeted protein, within the ER membrane. TMD1 alone provided a strong ER retention signal and TMD6 a weaker signal, but the other single TMD were unable to retain ICAM-1 in the ER. We conclude that TMD1 provides the first and sufficient signal for ER targeting of RyR1. The TMD outer pairs include redundant ER retention signals, with TMD1 providing the strongest signal.

Received for publication, March 22, 2007 , and in revised form, May 15, 2007.

^* This work was supported by the Biotechnology and Biological Sciences Research Council and the Wellcome Trust. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5 and Tables S1 and S2.

¹ Present address: Hutchison/Medical Research Council Research Centre, Hills Rd., Cambridge CB2 2ZX, UK.

² To whom correspondence should be addressed. Tel./Fax: 44-1223-334-058; E-mail: cwt1000{at}cam.ac.uk.

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