Cardiac RKIP induces a beneficial β-adrenoceptor–dependent positive inotropy

Abstract

In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the β1-adrenoceptor (β1AR). This result is unexpected, as β1AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the β2AR subtype. Analogously, RKIP deficiency exaggerates pressure overload-induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.

Is toxicant-induced Sertoli cell injury in vitro a useful model to study molecular mechanisms in spermatogenesis?

“…Collectively, these data suggest that p-FAK-Tyr 397 and p-FAK-Tyr 407 are crucial regulators of actin microfilaments at the ES, and they likely exert their effects on the intrinsic activity of Arp3, Eps8 and/or palladin (Figure 3) , plausibly via direct phosphorylation to activate these ABPs. These findings also implicate the possibility that these two FAK isoforms are useful therapeutic candidates to manage environmental toxicant-mediated Sertoli cell injury, such as via their overexpression using gene therapy approach as reported in men [155] and rodents [156] following industrial or accidental exposure to acute dose of some selected toxicants.…”

Local membrane charge regulates ல2 adrenergic receptor coupling to Gi

“…β1AR and β2AR signaling through Gs alters calcium handling in the cardiac myocyte, and increases the magnitude of Ca 2+ currents and Ca 2+ transients, which stimulate cardiac contraction 41,51 . However, elevated Ca 2+ concentrations also activate the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), which is implicated in structural remodeling that ultimately results in cardiac dysfunction [52][53][54][55][56] . Several lines of evidence suggest β2AR-Gi signaling keeps β2AR-Gs signaling in check via negative feedback: β2AR-Gi signaling occurs minutes after β2AR-Gs signaling 3 , β2AR-Gi signaling suppresses changes in calcium handling 51,57 , and β2AR-Gi signaling is anti-apoptotic 7,8 .…”

G Protein–Coupled Receptor Kinases: Crucial Regulators of Blood Pressure

“…In addition, a Gβγ binding site of GRK2 is also localized in the C‐terminal pleckstrin homology domain. Phosphorylated Raf kinase inhibitory protein binds to the N terminus of GRK2, resulting in the inhibition of its function …”

“…Phosphorylated Raf kinase inhibitory protein binds to the N terminus of GRK2, resulting in the inhibition of its function. 26 Distribution of GRK2. GRK2 is ubiquitously expressed in mammals.…”