Dual loss of regulator of G protein signaling 2 and 5 exacerbates ventricular myocyte arrhythmias and disrupts the fine-tuning of Gi/o signaling

Phosphodiesterases Mediate the Augmentation of Myogenic Constriction by Inhibitory G Protein Signaling and is Negatively Modulated by the Dual Action of RGS2 and 5

“… 62 In ventricular myocytes, the loss of only RGS2 or both RGS2 and 5 but not RGS5 alone leads to ventricular myocyte arrhythmias associated with decreased cAMP generation that is reversible by chemical inactivation of G i/o with PTX. 40 The results in this study also indicate that in the absence of NOS-generated nitric oxide, the modulation of G i/o activity by RGS2 and 5 to promote cAMP signaling is critical to preventing excessive myogenic response to changes in intraluminal pressure in the uterine vascular bed. And, besides the regulation of the canonical inhibition of cAMP generation by G i/o , we found a novel mechanism by which RGS2 and 5 promote cAMP signaling to modulate UA myogenic tone.…”

“…Others and we have reported that this effector antagonism between multiple RGS proteins is present in ventricular myocytes and the central nervous system. 40 , 62 In a previous study by Garzon and colleagues, it was reported that effector antagonism by RG-R7 is involved in the delayed tolerance associated with repeated morphine administration. That is, RGS-R7 proteins were found to bind G i/o/z proteins and sequester them, thereby preventing the acceleration of GTP hydrolysis necessary to restrict the amplitude of opioid analgesia by the more efficient RGS-R4 and RGS-Rz.…”

“… 38 , 39 Rgs2/5 dbKO mice were generated from crosses between Rgs2 −/− and Rgs5 −/− mice, as previously described. 40 All experiments were performed in accordance with the protocols approved by the Institutional Animal Care and Use Committee at Case Western Reserve University School of Medicine, in accordance with the National Institutes of Health Guidance for the Care and Use of Laboratory Animals.…”