The shortening of sarcomeres that co-ordinates the pump function of the heart is stimulated by electrically-mediated increases in [Ca2+]. This process of excitation-contraction coupling (ECC) is subject to modulation by neurohormonal mediators that tune the output of the heart to meet the needs of the organism. Endothelin-1 (ET-1) is a potent modulator of cardiac function with effects on contraction amplitude, chronotropy and automaticity. The actions of ET-1 are evident during normal adaptive physiological responses and increased under pathophysiological conditions, such as following myocardial infarction and during heart failure, where ET-1 levels are elevated. In myocytes, ET-1 acts through ETA- or ETB-G protein-coupled receptors (GPCRs). Although well studied in atrial myocytes, the influence and mechanisms of action of ET-1 upon ECC in ventricular myocytes are not fully resolved. We show in rat ventricular myocytes that ET-1 elicits a biphasic effect on fractional shortening (initial transient negative and sustained positive inotropy) and increases the peak amplitude of systolic Ca2+transients in adult rat ventricular myocytes. The negative inotropic phase was ETBreceptor-dependent, whereas the positive inotropic response and increase in peak amplitude of systolic Ca2+transients required ETAreceptor engagement. Both effects of ET-1 required phospholipase C (PLC)-activity, although distinct signalling pathways downstream of PLC elicited the effects of each ET receptor. The negative inotropic response involved inositol 1,4,5-trisphosphate (InsP3) signalling and protein kinase C epsilon (PKCε). The positive inotropic action and the enhancement in Ca2+transient amplitude induced by ET-1 were independent of InsP3signalling, but suppressed by PKCε. Serine 302 in cardiac myosin binding protein-C was identified as a PKCε substrate that when phosphorylated contributed to the suppression of contraction and Ca2+transients by PKCε following ET-1 stimulation. Thus, our data provide a new role and mechanism of action for InsP3and PKCε in mediating the negative inotropic response and in restraining the positive inotropy and enhancement in Ca2+transients following ET-1 stimulation.
Pharmacology, Toxicology and Pharmaceutical Science
2
7%
Agricultural and Biological Sciences
2
7%
Engineering
2
7%
Other
3
10%
Unknown
11
38%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 4. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 March 2018.
All research outputs
#11,439,980
of 34,376,207 outputs
Outputs from Journal of Molecular & Cellular Cardiology
#1,224
of 3,324 outputs
Outputs of similar age
#143,682
of 372,987 outputs
Outputs of similar age from Journal of Molecular & Cellular Cardiology
#11
of 36 outputs
Altmetric has tracked 34,376,207 research outputs across all sources so far. This one has received more attention than most of these and is in the 66th percentile.
So far Altmetric has tracked 3,324 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 5.2. This one has gotten more attention than average, scoring higher than 63% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 372,987 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 61% of its contemporaries.
We're also able to compare this research output to 36 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 69% of its contemporaries.
