Proper Restoration of Excitation-Contraction Coupling in the Dihydropyridine Receptor β1-null Zebrafish Relaxed Is an Exclusive Function of the β1a Subunit

被引:59
作者
Schredelseker, Johann [1 ]
Dayal, Anamika [1 ]
Schwerte, Thorsten [2 ]
Franzini-Armstrong, Clara [3 ]
Grabner, Manfred [1 ]
机构
[1] Innsbruck Med Univ, Div Biochem Pharmacol, Dept Med Genet Clin & Mol Pharmacol, A-6020 Innsbruck, Austria
[2] Univ Innsbruck, Inst Zool, A-6020 Innsbruck, Austria
[3] Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院;
关键词
II-III-LOOP; DYSGENIC SKELETAL-MUSCLE; CALCIUM-CHANNEL; CA2+ CURRENT; CHARGE MOVEMENTS; BETA-1A SUBUNIT; ALPHA(1S); EXPRESSION; ABSENCE; TRANSIENTS;
D O I
10.1074/jbc.M807767200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The paralyzed zebrafish strain relaxed carries a null mutation for the skeletal muscle dihydropyridine receptor (DHPR) beta(1a) subunit. Lack of beta(1a) results in (i) reduced membrane expression of the pore forming DHPR alpha(1S) subunit, (ii) elimination of alpha(1S) charge movement, and (iii) impediment of arrangement of the DHPRs in groups of four (tetrads) opposing the ryanodine receptor (RyR1), a structural prerequisite for skeletal muscle-type excitation-contraction (EC) coupling. In this study we used relaxed larvae and isolated myotubes as expression systems to discriminate specific functions of beta(1a) from rather general functions of beta isoforms. Zebrafish and mammalian beta 1a subunits quantitatively restored alpha(1S) triad targeting and charge movement as well as intracellular Ca2+ release, allowed arrangement of DHPRs in tetrads, and most strikingly recovered a fully motile phenotype in relaxed larvae. Interestingly, the cardiac/neuronal beta(2a) as the phylogenetically closest, and the ancestral housefly beta(M) as the most distant isoform to beta(1a) also completely recovered alpha(1S) triad expression and charge movement. However, both revealed drastically impaired intracellular Ca2+ transients and very limited tetrad formation compared with beta(1a). Consequently, larval motility was either only partially restored (beta(2a)-injected larvae) or not restored at all (beta(M)). Thus, our results indicate that triad expression and facilitation of 1,4-dihydropyridine receptor (DHPR) charge movement are common features of all tested beta subunits, whereas the efficient arrangement of DHPRs in tetrads and thus intact DHPR-RyR1 coupling is only promoted by the beta(1a) isoform. Consequently, we postulate a model that presents beta(1a) as an allosteric modifier of alpha(1S) conformation enabling skeletal muscle-type EC coupling.
引用
收藏
页码:1242 / 1251
页数:10
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