The idiopathic short QT syndrome (SQTS) is characterised by abbreviated QT intervals on the electrocardiogram and an increased risk of cardiac arrhythmia (Gussak et al, 2002). Recently, one form of SQTS has been linked to two different missense mutations in HERG (Human ether-a-go-go-related gene) leading to a common amino-acid substitution (N588K; asparagine to lysine) in the S5-Pore linker region of the HERG channel (Brugada et al, 2004). Data from recordings at ambient temperature of heterologously expressed N588K channels suggest that this amino acid change results in a loss of voltage-dependent inactivation and a consequent gain in HERG channel function (Brugada et al, 2004). The present study was conducted in order to determine characteristics of N588K channel current at a physiological temperature. The N588K mutation was made by a two-primer PCR approach and recombinant N588K-HERG channels were transiently expressed in Chinese Hamster Ovary (CHO) cells. Whole-cell patch-clamp recordings were made at 37^oC, using a potassium-based pipette dialysate. Two second duration voltage-clamp commands were applied from −80 mV to a range of test potentials in 10 mV increments. The end-pulse current-voltage relation for wild-type (WT) HERG current (I_HERG) was compared with that for N588K-HERG. WT I_HERG was maximal at ~0 to +10 mV and declined at more positive voltages (n = 5 cells). In contrast, within a physiologically relevant range of test potentials (up to ~ + 40 mV), N588K I_HERG continued to increase with progressive depolarisation (n = 5 cells). However, depolarisation to a highly positive voltage (+100 mV) resulted in a marked decline in I_HERG amplitude compared to + 40 mV (P<0.01; paired t test; n = 4 cells). These observations provide evidence that the N588K mutation does not eliminate I_HERG inactivation entirely, but rather shifts normal I_HERG rectification towards more positive voltages.