Effect of 5-HT4 receptor stimulation on the pacemaker current If in human isolated atrial myocytes

Abstract

A time-dependent, cesium-sensitive increasing inward current, that we had previously described having the electrophysiological properties of the pacemaker current I(f), was elicited by negative steps (-60 to -130 mV) from a holding potential of -40 mV. Boltzmann fit of control activation curves gave a midpoint (V1/2) of -88.9 +/- 2.6 mV (n = 14). 5-HT (1 microM) consistently caused a positive shift of V1/2 of 11.0 +/- 2.0 mV (n = 8, p < 0.001) of the activation curve toward less negative potentials, thus increasing the amount of current activated by clamp steps near the physiological maximum diastolic potential of these cells. The effect was dose-dependent, the EC50 being 0.14 microM. Maximum current amplitude was not changed by 5-HT. 5-HT did not increase I(f) amplitude when the current was maximally activated by cAMP perfused into the cell. The selective 5-HT4 antagonists, DAU 6285 (10 microM) and GR 125487 (1 microM), completely prevented the effect of 5-HT on I(f). The shift of V1/2 caused by 1 microM 5-HT in the presence of DAU 6285 or GR 125487 was 0.3 +/- 1 mV (n = 6) and 1.0 +/- 0.6 mV (n = 5), respectively (p < 0.01 versus 5-HT alone). The effect of 5-HT4 receptor blockade was specific, since neither DAU 6285 nor GR 125487 prevented the effect of 1 microM isoprenaline on I(f). Thus, 5-HT4 stimulation increases I(f) in human atrial myocytes; this effect may contribute to the arrhythmogenic action of 5-HT in human atrium.

Cardiac overexpression of the human 5-HT4receptor in mice

“…1). However, additional mechanisms, such as the action of 5-HT 4 receptors on pacemaker current in cardiomyocytes, could play an additional role (44,46). Reserpine (via extensive reduction of 5-HT levels in the heart) and a selective 5-HT 4 receptor antagonist (GR-125487) could significantly reduce the incidence of arrhythmias in cardiac preparations from TG mice.…”

“…This effect may be 5-HT 4 receptor mediated because the increase of pacemaker current (a current implied to mediate positive chronotropic effects in the sinus node) by 5-HT in isolated cardiomyocytes from the human atrium is sensitive to the appropriate receptor blockers (46).…”

Developmental Changes in Cardiomyocytes Differentiated from Human Embryonic Stem Cells: A Molecular and Electrophysiological Approach

“…I f is a diastolic current present in pacemaker, atrial, and ventricular CMs [16,22]. Four isoforms code for f-channels: hyperpolarization-activated cyclic nucleotide-gated potassium channel (HCN)-1, -2, -3, and -4 (for review, see [23]).…”

The Funny Current in Cardiac Non-Pacemaker Cells: Functional Role and Pharmacological Modulation

“…These are membrane-associated receptors coupled to guanylyl cyclase activity that increases intracellular 3'-5'-cyclic guanosine monophosphate nucleotide, which similarly to the adenosine cyclic nucleotide, binds to funny channels and increases the current. Accordingly, both serotonin and atrial natriuretic peptide proved to increase I f current in human atrial myocytes (Pino et al, 1998;. The effect is concentration-dependent and shows an affinity constant (Kd) quite similar to the physiological concentrations of serotonin and atrial natriuretic peptide likely reached upon adequate stimuli, i.e.…”