TY - JOUR
T1 - Rem-GTPase regulates cardiac myocyte L-type calcium current
AU - Magyar, Janos
AU - Kiper, Carmen E.
AU - Sievert, Gail
AU - Cai, Weikang
AU - Shi, Geng Xian
AU - Crump, Shawn M.
AU - Li, Liren
AU - Niederer, Steven
AU - Smith, Nic
AU - Andres, Douglas A.
AU - Satin, Jonathan
PY - 2012
Y1 - 2012
N2 - Rationale: The L-type calcium channels (LTCC) are critical for maintaining Ca2+-homeostasis. In heterologous expression studies, the RGK-class of Ras-related G-proteins regulates LTCC function; however, the physiological relevance of RGKLTCC interactions is untested. Objective: In this report we test the hypothesis that the RGK protein, Rem, modulates native Ca2+ current (ICa,L) via LTCC in murine cardiomyocytes. Methods and Results: Rem knockout mice (Rem-/-) were engineered, and ICa,L and Ca2+-handling properties were assessed. Rem-/- ventricular cardiomyocytes displayed increased ICa,L density. ICa,L activation was shifted positive on the voltage axis, and β-adrenergic stimulation normalized this shift compared with wild-type ICa,L. Current kinetics, steady-state inactivation and facilitation was unaffected by Rem-/-. Cell shortening was not significantly different. Increased ICa,L density in the absence of frank phenotypic differences motivated us to explore putative compensatory mechanisms. Despite the larger ICa,L density, Rem-/- cardiomyocyte Ca2+ twitch transient amplitude was significantly less than that compared with wild type. Computer simulations and immunoblot analysis suggests that relative dephosphorylation of Rem-/- LTCC can account for the paradoxical decrease of Ca2+ transients. Conclusions: This is the first demonstration that loss of an RGK protein influences ICa,L in vivo in cardiac myocytes.
AB - Rationale: The L-type calcium channels (LTCC) are critical for maintaining Ca2+-homeostasis. In heterologous expression studies, the RGK-class of Ras-related G-proteins regulates LTCC function; however, the physiological relevance of RGKLTCC interactions is untested. Objective: In this report we test the hypothesis that the RGK protein, Rem, modulates native Ca2+ current (ICa,L) via LTCC in murine cardiomyocytes. Methods and Results: Rem knockout mice (Rem-/-) were engineered, and ICa,L and Ca2+-handling properties were assessed. Rem-/- ventricular cardiomyocytes displayed increased ICa,L density. ICa,L activation was shifted positive on the voltage axis, and β-adrenergic stimulation normalized this shift compared with wild-type ICa,L. Current kinetics, steady-state inactivation and facilitation was unaffected by Rem-/-. Cell shortening was not significantly different. Increased ICa,L density in the absence of frank phenotypic differences motivated us to explore putative compensatory mechanisms. Despite the larger ICa,L density, Rem-/- cardiomyocyte Ca2+ twitch transient amplitude was significantly less than that compared with wild type. Computer simulations and immunoblot analysis suggests that relative dephosphorylation of Rem-/- LTCC can account for the paradoxical decrease of Ca2+ transients. Conclusions: This is the first demonstration that loss of an RGK protein influences ICa,L in vivo in cardiac myocytes.
KW - Calcium current
KW - L-type calcium channel
KW - Patch-clamp
KW - Ras-GTPase
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U2 - 10.4161/chan.20192
DO - 10.4161/chan.20192
M3 - Article
C2 - 22854599
AN - SCOPUS:84864415182
SN - 1933-6950
VL - 6
SP - 166
EP - 173
JO - Channels
JF - Channels
IS - 3
ER -