Skeletal muscle excitation-contraction coupling is independent of a conserved heptad repeat motif in the C-terminus of the DHPRbeta(1a) subunit.
In skeletal muscle excitation-contraction (EC) coupling the sarcolemmal L-type Ca(2+) channel or 1,4-dihydropyridine receptor (DHPR) transduces the membrane depolarization signal to the sarcoplasmic Ca(2+) release channel RyR1 via protein-protein interaction. While it is evident that the pore-forming and voltage-sensing DHPRalpha(1S) subunit is essential for this process, the intracellular DHPRbeta(1a) subunit was also shown to be indispensable. We previously found that the beta(1a) subunit is essential to target the DHPR into groups of four (tetrads) opposite the RyR1 homotetramers, a prerequisite for skeletal muscle EC coupling. Earlier, a unique hydrophobic heptad repeat motif (Lcdots, three dots, centeredVcdots, three dots, centeredV) in the C-terminus of beta(1a) was postulated by others to be essential for skeletal muscle EC coupling, as substitution of these residues with alanines resulted in 80% reduction of RyR1 Ca(2+) release. Therefore, we wanted to address the question if the proposed beta(1a) heptad repeat motif could be an active element of the DHPR-RyR1 signal transduction mechanism or already contributes at the ultrastructural level i.e. DHPR tetrad arrangement. Surprisingly, our experiments revealed full tetrad formation and an almost complete restoration of EC coupling in beta(1)-null zebrafish relaxed larvae and isolated myotubes upon expression of a beta(1a)-specific heptad repeat mutant (LVV to AAA) and thus contradict the earlier results.
Dayal
Anamika
A
Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Austria.
Schredelseker
Johann
J
Franzini-Armstrong
Clara
C
Grabner
Manfred
M
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D056966:Excitation Contraction Coupling; D055786:Gene Knockout Techniques; D007814:Larva / Q000166:cytology / Q000378:metabolism; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D016415:Sequence Alignment; D015027:Zebrafish / Q000254:growth & development / Q000378:metabolism
D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium
J Biol Chem. 2009 Jan 9;284(2):1242-51
19008220
Nature. 1987 Feb 19-25;325(6106):717-20
2434854
Neuron. 2000 Jan;25(1):177-90
10707982
Biophys J. 2003 Jan;84(1):220-37
12524277
Neuron. 2004 May 13;42(3):387-99
15134636
Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17219-24
16286639
Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5658-63
20212109
Curr Opin Neurobiol. 2003 Jun;13(3):298-307
12850214
FEBS Lett. 1999 Feb 26;445(2-3):366-70
10094491
Nature. 1990 Aug 9;346(6284):567-9
2165570
Nature. 1990 Aug 9;346(6284):569-72
2165571
J Exp Biol. 2000 Jun;203(Pt 11):1659-69
10804156
Nature. 2004 Jun 10;429(6992):675-80
15170217
Circ Res. 1996 Aug;79(2):358-62
8756015
Mol Biol Cell. 2004 Dec;15(12):5408-19
15385628
Physiol Rev. 1997 Jul;77(3):699-729
9234963
Cell Calcium. 2006 Mar;39(3):227-36
16368137
J Cell Biol. 1988 Dec;107(6 Pt 2):2587-600
2849609
J Cell Biol. 1995 May;129(3):659-71
7730402
Nature. 1973 Mar 23;242(5395):244-6
4540479
Nature. 2004 Jun 10;429(6992):671-5
15141227
J Bioenerg Biomembr. 2003 Dec;35(6):599-620
15000522
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13961-6
8943043
Biophys J. 2004 Aug;87(2):929-42
15298900
Biochim Biophys Acta. 1972 Jun 23;267(3):605-8
4537984
Biophys J. 1999 Dec;77(6):2953-67
10585919
J Cell Biol. 1993 Dec;123(5):1161-74
8245124
Biol Res. 2004;37(4):565-75
15709683
Science. 1999 Nov 19;286(5444):1583-7
10567269