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Properties of the funny current ( I  f ) have been studied in several animal and cellular models, but so far little is known concerning its properties in human pacemaker cells. This work provides a detailed characterization of  I  f  in human-induced pluripotent stem cell (iPSC)–derived pacemaker cardiomyocytes (pCMs), at different time points. Patch-clamp analysis showed that  I  f  density did not change during differentiation; however, after day 30, it activates at more negative potential and with slower time constants. These changes are accompanied by a slowing in beating rate.  I  f  displayed the voltage-dependent block by caesium and reversed ( E  rev ) at − 22 mV, compatibly with the 3:1 K + /Na +  permeability ratio. Lowering [Na + ] o  (30 mM) shifted the  E  rev  to − 39 mV without affecting conductance. Increasing [K + ] o  (30 mM) shifted the  E  rev  to − 15 mV with a fourfold increase in conductance. pCMs express mainly  HCN4  and  HCN1  together with the accessory subunits CAV3, KCR1, MiRP1, and SAP97 that contribute to the context-dependence of  I  f . Autonomic agonists modulated the diastolic depolarization, and thus rate, of pCMs. The adrenergic agonist isoproterenol induced rate acceleration and a positive shift of  I  f  voltage-dependence (EC 50  73.4 nM). The muscarinic agonists had opposite effects (Carbachol EC 50 , 11,6 nM). Carbachol effect was however small but it could be increased by pre-stimulation with isoproterenol, indicating low cAMP levels in pCMs. In conclusion, we demonstrated that pCMs display an  I  f  with the physiological properties expected by pacemaker cells and may thus represent a suitable model for studying human  I  f -related sinus arrhythmias.

pflügers archiv für die gesamte physiologie des menschen und der tiere/pflügers archiv

A detailed characterization of the hyperpolarization-activated “funny” current (If) in human-induced pluripotent stem cell (iPSC)–derived cardiomyocytes with pacemaker activity