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MBC in Press, published online ahead of print September 22, 2004
Mol. Biol. Cell 10.1091/mbc.E04-05-0414

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Submitted on May 19, 2004
Accepted on September 8, 2004

Differential Contribution of Skeletal and Cardiac II-III Loop Sequences to the Assembly of DHP-Receptor Arrays in Skeletal Muscle

Hiroaki Takekura,*{dagger}{ddagger} Cecilia Paolini,*{dagger}{sect} Clara Franzini-Armstrong,{dagger} Gerlinde Kugler,||¶ Manfred Grabner,|| and Bernhard E. Flucher¶#

{dagger}Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104; ||Department of Medical Genetics, Molecular and Clinical Pharmacology, and Department of Physiology and Medical Physics, Innsbruck Medical University, A-6020 Innsbruck, Austria

Monitoring Editor: Daniel Goodenough

The plasmalemmal dihydropyridine receptor (DHPR) is the voltage sensor in skeletal muscle excitation-contraction (e-c) coupling. It activates calcium release from the sarcoplasmic reticulum via protein-protein interactions with the ryanodine receptor (RyR). To enable this interaction DHPRs are arranged in arrays of tetrads opposite RyRs. In the DHPR {alpha}1S subunit the cytoplasmic loop connecting repeats II and III is a major determinant of skeletal-type e-c coupling. Whether the essential II-III loop sequence (L720-L764) also determines the skeletal-specific arrangement of DHPRs was examined in dysgenic ({alpha}1S-null) myotubes reconstituted with distinct {alpha}1 subunit isoforms and II-III loop chimeras. Parallel immunofluorescence and freeze-fracture analysis showed that {alpha}1S and chimeras containing L720-L746, all of which restored skeletal-type e-c coupling, displayed the skeletal arrangement of DHPRs in arrays of tetrads. Conversely, {alpha}1C and those chimeras with a cardiac II-III loop and cardiac e-c coupling properties were targeted into junctional membranes but failed to form tetrads. However, an {alpha}1S-based chimera with the heterologous Musca II-III loop produced tetrads but did not reconstitute skeletal muscle e-c coupling. These findings suggest an inhibitory role in tetrad formation of the cardiac II-III loop, and that the organization of DHPRs in tetrads vis-à-vis the RyR is necessary but not sufficient for skeletal-type e-c coupling.

*These two authors contributed equally to this work.

Present addresses: {ddagger}Department of Physiological Sciences, National Institute of Fitness and Sports, Kanoya, Kagoshima, 891-2393 Japan; {sect}Ce.S.I. Center for Research on Aging, Fondazione "G.d’Annunzio", Chieti, Italy.

#Corresponding author. E-mail: Bernhard.e.flucher{at}uibk.ac.at






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