کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8474770 | 1550431 | 2014 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Adenylyl cyclase-mediated effects contribute to increased Isoprenaline-induced cardiac contractility in TRPM4-deficient mice
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موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیولوژی سلول
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Adenylyl cyclase-mediated effects contribute to increased Isoprenaline-induced cardiac contractility in TRPM4-deficient mice Adenylyl cyclase-mediated effects contribute to increased Isoprenaline-induced cardiac contractility in TRPM4-deficient mice](/preview/png/8474770.png)
چکیده انگلیسی
TRPM4 and TRPM5 proteins belong to the Transient Receptor Potential (TRP) ion channel family and form Ca2 +-activated nonselective cation channels. Recently we showed a significant increase of Isoprenaline-induced inotropy in TRPM4-deficient (Trpm4â/â) mice. This is caused by increased Ca2 + entry via L-type calcium channels due to faster action potential repolarization in Trpm4â/â ventricular myocytes [Mathar et al., 2013]. Here, we investigated the contribution of various steps of the β-adrenergic signalling cascade to the augmented positive inotropic response in the absence of TRPM4, and whether the closely related TRPM5 additively contributes to this process using TRPM4/TRPM5-double deficient (Trpm4/Trpm5(â/â)2) mice. We performed contractility measurements on isolated papillary muscles from wild type, Trpm4â/â and Trpm4/Trpm5(â/â)2 mice. As shown in Trpm4â/â mice, Isoprenaline-induced inotropy in Trpm4/Trpm5(â/â)2 papillary muscles was significantly increased compared to wild type, whereas basal, frequency- and Ca2 +-dependent contractility was unaltered. Equivalent to Isoprenaline, activation of adenylyl cyclase using Forskolin led to a significantly increased twitch force in Trpm4â/â heart preparations whereas the Isoprenaline-mediated increase in cAMP level was comparable to wild type mice. Notably, the positive inotropic response evoked by phosphodiesterase inhibition with 3-isobutyl-1-methylxanthine (IBMX) was unchanged between both genotypes. Furthermore, experiments performed with increasing concentrations of IBMX after prestimulation with Forskolin and vice versa did not provide evidence that the increased β-adrenergic positive inotropic response in TRPM4-deficient papillary muscles is due to differences in accumulation of cAMP. Compared to inhibition of phosphodiesterase, the rise of intracellular cAMP by activating adenylyl cyclase is accompanied by ATP breakdown. To test the relevance of TRPM4 during forced ATP consumption we measured contractility under ischemic conditions. Here, Trpm4â/â papillary muscles showed improved contractile function in comparison to wild type. Our results are consistent with the hypothesis that TRPM4 has a limiting effect on cardiac contractility specifically in ATP depleting conditions. The increased positive inotropic response in Trpm4â/â papillary muscles evoked by stimulation of adenylyl cyclase activity is not observed without active enhancement of ATP hydrolysis. Furthermore, the contractility of Trpm4â/â papillary muscles was also increased during ischemic simulation. These data underscore the potential of TRPM4 inactivation as an approach to increase inotropy in specific conditions associated with increased catecholamine levels, such as heart failure and ischemia.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular and Cellular Cardiology - Volume 74, September 2014, Pages 307-317
Journal: Journal of Molecular and Cellular Cardiology - Volume 74, September 2014, Pages 307-317
نویسندگان
Sebastian Uhl, Ilka Mathar, Rudi Vennekens, Marc Freichel,