Modulation of potassium channels in the hearts of transgenic and mutant mice with altered polyamine biosynthesis

Inward rectification of cardiac I-K1 channels was modulated by genetic manipulation of the naturally occurring polyamines. Ornithine decarboxylase (ODC) was overexpressed in mouse heart under central of the cardiac alpha -myosin heavy chain promoter (alpha MHC). In ODC transgenic hearts, putrescine and cadaverine levels were highly elevated (similar to 35-fold for putrescine), spermidine was increased 3.6-fold, but spermine was essentially unchanged. I-K1 density was reduced by similar to 38%, although the voltage-dependence of rectification was essentially unchanged. Interestingly the fast component of transient outward (I-to,I-f) current was increased, but the total outward current amplitude was unchanged. I-K1 and I-to currents were also studied in myocytes from mutant Gyro (Gy) mice in which the spermine synthase gene is disrupted, leading to a complete loss of spermine. I-K1 current densities were not altered in Gy myocytes, but the steepness of rectification was reduced indicating a role for spermine in controlling rectification. Intracellular dialysis of myocytes with putrescine, spermidine and spermine caused reduction, no change and increase of the steepness of rectification, respectively. Taken together with kinetic analysis of I-K1 activation these results are consistent with spermine being a major rectifying factor at potentials positive to E-K, spermidine dominating at potentials around and negative to E-K, and putrescine playing no significant role in rectification in the mouse heart. (C) 2000 Academic Press.