I _f Current and Spontaneous Activity in Mouse Embryonic Ventricular Myocytes

Abstract

Knowledge of the initiation of electrical and contractile activity in the embryonic heart relies to a large extent on data obtained in chicken. In recent years, molecular biological techniques have raised an interest in mouse physiology, including early embryonic development. We studied action potentials and the occurrence of one of the pacemaker currents, I(f), by the whole-cell voltage and current-clamp technique at the earliest stage at which a regular heartbeat is established (9.5 days postcoitum) and at 1 day before birth. We show, first, that at the early stage there is a prominent I(f) in mouse embryonic ventricles, which decreases by 82% before birth in concert with the loss of regular spontaneous activity of ventricular cells. Second, the decrease in I(f) current is associated with a slight change in channel gating kinetics and a decrease in total mRNA expression of the genes encoding for I(f) current. Third, the most prevalent mRNA subtype is switched from HCN4 to HCN2 during the second half of embryonic development. Fourth, the I(f) current may be modulated by the beta-adrenergic cascade, although the coupling to the beta-adrenoceptor in the sarcolemma itself is not yet mature. We conclude that I(f) current of the sinus node type is present in early embryonic mouse ventricular cells. In association with a loss of I(f) current, the ventricle tends to lose pacemaker potency during the second half of embryonic development.

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

“…A minority of myocytes isolated from the hearts of adult rats express I f , which, when present, was of small amplitude. In accordance with data reported in the fetal mouse (Yasui et al, 2001;Mommersteeg et al, 2007;Schweizer et al, 2009), expression analysis in the rat documented that both HCN4 and HCN2 isoforms account for the majority of total HCN transcript in the neonatal ventricle, while HCN1 and HCN3 isoforms are not expressed at detectable levels . Interestingly, HCN4 is down-regulated during rat heart maturation, but in association with HCN2 it undergoes a clear-cut up-regulation after cardiac infarction (Suffredini et al, 2009).…”

Prenatal exposure to carbon monoxide delays postnatal cardiac maturation

“…7,14,15 A higher expression of HCN4 was detected in CO-exposed rat hearts at 4 days after birth (2.73±0.54 vs 1.04±0.11) (Figure 5a); this was accompanied by a relative upregulation of the mRNA coding for MinK-related peptide 1 (MiRP-1) (2.06 ± 0.02 vs 1.03 ± 0.2 at 4 days) (Figure 5c). MiRP-1 is a b-subunit that enhances the expression and speeds up the kinetics of activation of the HCN-derived proteins; in the adult heart, MiRP-1 is expressed in the sinus node region but hardly detectable in the ventricle.…”

“…To get a functional correlate, we evaluated the temporal pattern of expression of f-current. In fact, I f is overexpressed in rodent ventricular myocytes during the fetal life but is downregulated after birth 13,14 ; eventually, I f expression is reinduced when adult cardiomyocytes undergo 'pathological' hypertrophic growth such as in cardiac diseases. 8 Figure 3 shows typical action potentials (upper panels) and currents (lower panels) recorded in myocytes isolated from control and CO-exposed rat hearts at 2 (panels a and b) and 40 (panels c and d) days after birth.…”

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

“…Molecularly, the extinction of Tbx3 leads to the appearance of "high conductance" proteins [11][12][13] , such as the connexins Cx40 and Cx43 [14] , and the replacement of the Land T-type Ca 2+ channels by the fast voltage-activated sodium channel Scn5a (Nav1.5) [15] . HCN4 expression is also strongly decreased in the working myocardium, as this tissue loses its intrinsic pacemaker activity [16][17][18] . The ventricular conduction is provided by the trabecular myocardium from the dorsal part of atrioventricular canal, which expresses the fast-conducting connexins [19,20] .…”