title: Mechanism of pacemaking in I(K1)-downregulated myocytes.
abstract: Biological pacemakers were recently created by genetic suppression of inward rectifier potassium current, I(K1), in guinea pig ventricular cells. We simulated these cells by adjusting I(K1) conductance in the Luo-Rudy model of the guinea pig ventricular myocyte. After 81% I(K1) suppression, the simulated cell reached steady state with pacemaker period of 594 ms. Pacemaking current is carried by the Na+-Ca2+ exchanger, I(NaCa), which depends on the intracellular calcium concentration [Ca2+]i. This [Ca2+]i dependence suggests responsiveness (increase in rate) to beta-adrenergic stimulation (betaAS), as observed experimentally. Simulations of betaAS demonstrate such responsiveness, which depends on I(NaCa) expression. However, a simultaneous betaAS-mediated increase in the slow delayed rectifier, I(Ks), limits betaAS sensitivity.
authors.affiliation: Cardiac Bioelectricity Research and Training Center, Case Western Reserve University, Cleveland, Ohio 44106-7207, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Silva
authors.forename: Yoram
authors.initials: Y
authors.lastname: Rudy
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D011188:Potassium; D002118:Calcium