286 AMINO ACID MUTATIONS IN THE MOUSE CALDESMON C-TERMINAL FUNCTIONAL DOMAIN CAUSES DETRUSOR OVERACTIVITY DURING THE FILLING PHASE OF THE BLADDER

Abstract

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology (I)1 Apr 2013286 AMINO ACID MUTATIONS IN THE MOUSE CALDESMON C-TERMINAL FUNCTIONAL DOMAIN CAUSES DETRUSOR OVERACTIVITY DURING THE FILLING PHASE OF THE BLADDER Maoxian Deng, Boopathi Ettickan, Joseph Hypolite, Tobias Raabe, Shaohua Chang, Stephen Zderic, and Samuel Chacko Maoxian DengMaoxian Deng Glenolden, PA More articles by this author , Boopathi EttickanBoopathi Ettickan Glenolden, PA More articles by this author , Joseph HypoliteJoseph Hypolite Glenolden, PA More articles by this author , Tobias RaabeTobias Raabe Philadelphia, PA More articles by this author , Shaohua ChangShaohua Chang Glenolden, PA More articles by this author , Stephen ZdericStephen Zderic Philadelphia, PA More articles by this author , and Samuel ChackoSamuel Chacko Glenolden, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1670AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Partial bladder outlet obstruction (PBOO) leads to remodeling of the detrusor smooth muscle (DSM) and hypertrophy. Hypertrophied DSM reveals alterations in the contractile and regulatory proteins and detrusor overactivity and overactive bladder. 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 CaD functional domain that inhibits the actomyosin ATPase leads to diminished CaD-induced inhibition of actin-actin-activated ATP hydrolysis by myosin. This study was conducted to determine if mutation of the ATPase inhibitory domain in the CaD alter the contractile characteristics of DSM during the resting phase of the bladder and during voiding contraction. METHODS Transgenic mice with mutations of 5 amino acid residues (Lys523 to Gln, Val524 to Leu, Ser526 to Thr, Pro527 to Cys, and Lys529 to Ser), which encompasses part of the tropomyosin-binding and ATPase inhibitory determinants located in exon 12, were generated by homologous recombination. RESULTS The homozygous (−/−) animals did not develop, but heterozygous (−/+) mice, carrying the expected mutations, matured and reproduced normally. The bladder from −/+ mice were slightly hypertrophied compared to WT. The force produced by DSM strips from −/+ mice in response to KCl and electrical field stimulation was 40-60% more than that of the WT. Furthermore, −/+ mice revealed non-voiding bladder contractions during the bladder filling phase on awake cystometry, indicating that the CaD ATPase inhibitory site suppresses force generation during bladder filling and changing the amino acid sequence in 50% of the CaD partially releases the suppression of force generation. CONCLUSIONS Our data show for the first time a functional phenotype, at the tissue and organ level in vivo, following mutation of the CaD ATPase inhibitory domain. Furthermore, homozygosity for mutation of the ATPase inhibitory site appears to be lethal for embryonic development. The CaD mutant mouse line might serve as a model for detrusor overactivity and overactive bladder. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e116-e117 Peer Review Report Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Maoxian Deng Glenolden, PA More articles by this author Boopathi Ettickan Glenolden, PA More articles by this author Joseph Hypolite Glenolden, PA More articles by this author Tobias Raabe Philadelphia, PA More articles by this author Shaohua Chang Glenolden, PA More articles by this author Stephen Zderic Philadelphia, PA More articles by this author Samuel Chacko Glenolden, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...