DEFECTIVE PACEMAKER CURRENT (I-H) IN A ZEBRAFISH MUTANT WITH A SLOW HEART-RATE

At a cellular level, cardiac pacemaking, which sets the rate and rhyth m of the heartbeat, is produced by the slow membrane depolarization th at occurs between action potentials, Several ionic currents could acco unt for this pacemaker potential, but their relative pi-eminence is co ntroversial, and it is not known which ones actually play a pacemaking role ire vivo. To correlate currents in individual heart cells with t he rhythmic properties of the int-act heart, we have examined slow mo (smo), a recessive mutation we discovered in the zebrafish Danio I el io. This mutation causes a reduced heart rate in the embryo, a propert y we can quantitate because the embryo is transparent, We developed me thods for culture of cardiocytes from zebrafish embryos and found that , even in culture, cells from smo continue to beat relatively slowly, By patch-clamp analysis, we discovered that a large repertoire of card iac currents noted in other species are present in these cultured cell s, including sodium, T-type, and L-type calcium and several potassium currents, all of which appear normal in the mutant, The only abnormali ty appears to be in a hyperpolarization-activated inward current with the properties of I-h, a current described previously in the nervous s ystem, pacemaker, and other cardiac tissue, smo cardiomyocytes have a reduction in I-h that appears to result from severe diminution of one kinetic component of the I-h current. This provides strong evidence th at I-h is an important contributor to the pacemaking behavior of the i ntact heart.