Amino acid mutations in the caldesmon COOH-terminal functional domain increase force generation in bladder smooth muscle

作者：Deng Maoxian; Boopathi Ettickan; Hypolite Joseph A; Raabe Tobias; Chang Shaohua; Zderic Stephen; Wein Alan J; Chacko Samuel^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2013, 305(10): F1455-F1465.

DOI：10.1152/ajprenal.00174.2013

• actin
• myosin ATPase
• thin filament
• smooth muscle cell
• detrusor overactivity

Amino acid mutations in the caldesmon COOH-terminal functional domain increase force generation in bladder smooth muscle. Am J Physiol Renal Physiol 305: F1455-F1465, 2013. First published September 28, 2013; doi:10.1152/ajprenal.00174.2013.-Caldesmon (CaD), a component of smooth muscle thin filaments, binds actin, tropomyosin, calmodulin, and myosin and inhibits actin-activated ATP hydrolysis by smooth muscle myosin. Internal deletions of the chicken CaD functional domain that spans from amino acids (aa) 718 to 731, which corresponds to aa 512-530 including the adjacent aa sequence in mouse CaD, lead to diminished CaD-induced inhibition of actin-activated ATP hydrolysis by myosin. Transgenic mice with mutations of five aa residues (Lys(523) to Gln, Val(524) to Leu, Ser(526) to Thr, Pro(527) to Cys, and Lys(529) to Ser), which encompass the ATPase inhibitory determinants located in exon 12, were generated by homologous recombination. Homozygous (-/-) animals did not develop, but heterozygous (+/-) mice carrying the expected mutations in the CaD ATPase inhibitory domain (CaD mutant) matured and reproduced normally. The peak force produced in response to KCl and electrical field stimulation by the detrusor smooth muscle from the CaD mutant was high compared with that of the wild type. CaD mutant mice revealed nonvoiding contractions during bladder filling on awake cystometry, suggesting that the CaD ATPase inhibitory domain suppresses force generation during the filling phase and this suppression is partially released by mutations in 50% of CaD in heterozygous. Our data show for the first time a functional phenotype, at the intact smooth muscle tissue and in vivo organ levels, following mutation of a functional domain at the COOH-terminal region of CaD.

• 出版日期2013-11