Altered heart rate and sinoatrial node function in mice lacking the cAMP regulator phosphoinositide 3-kinase-gamma.
Ablation of the enzyme phosphoinositide 3-kinase (PI3K)gamma (PI3Kgamma(-/-)) in mice increases cardiac contractility by elevating intracellular cAMP and enhancing sarcoplasmic reticulum Ca(2+) handling. Because cAMP is a critical determinant of heart rate, we investigated whether heart rate is altered in mice lacking PI3Kgamma. Heart rate was similar in anesthetized PI3Kgamma(-/-) and wild-type (PI3Kgamma(+/+)) mice. However, IP injection of atropine (1 mg/kg), propranolol (1 mg/kg), or both drugs in combination unmasked elevated heart rates in PI3Kgamma(-/-) mice, suggesting altered sinoatrial node (SAN) function. Indeed, spontaneous action potential frequency was approximately 35% greater in SAN myocytes isolated from PI3Kgamma(-/-) mice compared with PI3Kgamma(+/+) mice. These differences in action potential frequency were abolished by intracellular dialysis with the cAMP/protein kinase A antagonist Rp-cAMP but were unaffected by treatment with ryanodine to inhibit sarcoplasmic reticulum Ca(2+) release. Voltage-clamp experiments demonstrated that elevated action potential frequencies in PI3Kgamma(-/-) SAN myocytes were more strongly associated with cAMP-dependent increases in L-type Ca(2+) current (I(Ca,L)) than elevated hyperpolarization-activated current (I(f)). In contrast, I(Ca,L) was not increased in working atrial myocytes, suggesting distinct subcellular regulation of L-type Ca(2+) channels by PI3Kgamma in the SAN compared with the working myocardium. In summary, PI3Kgamma regulates heart rate by the cAMP-dependent modulation of SAN function. The effects of PI3Kgamma ablation in the SAN are unique from those in the working myocardium.
Rose
Robert A
RA
Department of Physiology, University of Toronto, Ontario, Canada.
Kabir
M Golam
MG
Backx
Peter H
PH
D000200:Action Potentials / Q000235:genetics; D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000242:Cyclic AMP / Q000502:physiology*; D006339:Heart Rate / Q000235:genetics*; D007527:Isoenzymes / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D012849:Sinoatrial Node / Q000201:enzymology* / Q000503:physiopathology*
D007527:Isoenzymes; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse