Rebuttal: What If the shoe doesn't fit? “The funny current has a major pacemaking role in the sinus node”

The concept that If is the most important pacemaker current has been widely promulgated since the late 1970s, and accordingly, has been widely accepted by a generation of pacemaker researchers and educators. Indeed, hyperpolarization-activated and cAMP-modulated-If manifests features apt to generate diastolic depolarization (DD) and mediate autonomic rate modulation. But sarcolemmal ion channels and proteins involved in intracellular Ca2+ balance/cycling operate together as a system. For example, inward INCX, is also activated by hyperpolarization, and is additionally regulated by intracellular [Ca2+] changes (triggered by the action potential and also occurring spontaneously via ryanodine receptors, RyRs, during DD). INCX is also larger in amplitude and activates much more rapidly than If. Autonomic stimulation enhances PKA- and CaMKII-dependent phosphorylation of sarcolemmal ion channels (e.g. ICaL, IK) and Ca2+cycling proteins (e.g. phospholamban, RyRs) leading to changes in membrane potential and cell Ca2+balance/cycling. The hypothesis that a coupled-clock system regulates basal automaticity and its response to neurotransmitters poses a formidable challenge to the concept that If is the pacemaker mechanism. “New evidence” (Himeno et al.AJP;2011;300:H251–H261) against the coupled-clock hypothesis, cited by DiFrancesco and Noble (Heart Rhythm;2011), neither measured [Ca2+], nor addressed a role of If, and has been refuted on technical grounds (Maltsev et al.AJP;2011;300:H2323–H2324). While DiFrancesco and Noble point out that If properties are “just right” for a specific role in pacemaker function, they fail to state exactly what this role is. The voltage- and cAMP-dependence of If does not prove that it is unique for pacemaker rate regulation, because the mechanisms mentioned above overlap If and are also “just right” for pacemaker rate regulation. A unique role of If in rate regulation certainly does not follow from the facts that funny-channels are: (i) specifically expressed in pacemaker cells; (ii) a marker of developing pacemaker tissue; (iii) exploited for “biological” pacemakers”. Additional “evidence” cited by DiFrancesco and Noble (Fig.A), like numerous prior studies in which If was genetically manipulated in mice (Fig.B–E), actually confirms that If is not necessary for rate acceleration in response to autonomic stimulation or exercise. In contrast, numerous studies demonstrate that when the coupled-clock system is impaired, either genetically or pharmacologically, with If intact, β-AR-mediated rate acceleration is markedly compromised (cf. review Vinogradova-Lakatta;JMCC;2009;47:456–474) indicating that If is also not sufficient for rate acceleration. Mechanisms overlapping If function, however, appear to be both necessary and sufficient for rate acceleration (cf. review Lakatta et al.Circ Res;2010;106:659–673). Figure Autonomic heart rate modulation is preserved in genetically manipulated mice with deficient If function Is there a specific role for If in rate regulation? Numerous studies in many species, including humans, have demonstrated that pharmacologic inhibition of If causes a modest bradycardia. Thus, the only documented specific role for If in pacemaking is to prevent modest bradycardia. (Deep bradycardia, conduction defects, and high mortality of the tamoxifen-induced HCN4 knockout in mice in Fig.A-study were not manifested in Fig.B-study which used much lower doses of tamoxifen). We conclude that “the Cinderella pacemaking shoe” does not fit If! If, functioning together with its “team-mates” within a coupled-clock system, provides modest protection against bradycardia rather than regulates action potential firing rate acceleration.