title: Ca2+ influx through T- and L-type Ca2+ channels have different effects on myocyte contractility and induce unique cardiac phenotypes.
abstract: T-type Ca(2+) channels (TTCCs) are expressed in the developing heart, are not present in the adult ventricle, and are reexpressed in cardiac diseases involving cardiac dysfunction and premature, arrhythmogenic death. The goal of this study was to determine the functional role of increased Ca(2+) influx through reexpressed TTCCs in the adult heart. A mouse line with cardiac-specific, conditional expression of the alpha1G-TTCC was used to increase Ca(2+) influx through TTCCs. alpha1G hearts had mild increases in contractility but no cardiac histopathology or premature death. This contrasts with the pathological phenotype of a previously studied mouse with increased Ca(2+) influx through the L-type Ca(2+) channel (LTCC) secondary to overexpression of its beta2a subunit. Although alpha1G and beta2a myocytes had similar increases in Ca(2+) influx, alpha1G myocytes had smaller increases in contraction magnitude, and, unlike beta2a myocytes, there were no increases in sarcoplasmic reticulum Ca(2+) loading. Ca(2+) influx through TTCCs also did not induce normal sarcoplasmic reticulum Ca(2+) release. alpha1G myocytes had changes in LTCC, SERCA2a, and phospholamban abundance, which appear to be adaptations that help maintain Ca(2+) homeostasis. Immunostaining suggested that the majority of alpha1G-TTCCs were on the surface membrane. Osmotic shock, which selectively eliminates T-tubules, induced a greater reduction in L- versus TTCC currents. These studies suggest that T- and LTCCs are in different portions of the sarcolemma (surface membrane versus T-tubules) and that Ca(2+) influx through these channels induce different effects on myocyte contractility and lead to distinct cardiac phenotypes.
authors.affiliation: Department of Physiology, Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa., USA.
authors.forename: Naser
authors.initials: N
authors.lastname: Jaleel
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.forename: Scott
authors.initials: S
authors.lastname: MacDonnell
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Remus
authors.initials: R
authors.lastname: Berretta
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Leanne
authors.initials: L
authors.lastname: Cribbs
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000096:biosynthesis* / Q000235:genetics; D020747:Calcium Channels, T-Type / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity / Q000502:physiology; D051381:Rats; D012508:Sarcolemma / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
chemical_list: D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium