Ca2+-activated adenylyl cyclase 1 introduces Ca2+-dependence to beta-adrenergic stimulation of HCN2 current

Atrial chronotropic reactivity to catecholamines in neonatal rats: Contribution of β-adrenoceptor subtypes

“…Additionally, neonatal atria behaved as adult preparations regarding the R max to agonists that act downstream the adrenoceptor-G s interaction, namely forskolin and IBMX. Indeed, sensitivity to forskolin was greater in neonates than in adults, which might be related to greater expression of AC-1 (the isoform majorly involved in stimulation in the pacemaker current I f ; Kryukova et al, 2012) in the former, if protein levels parallel those of its transcript, as it is the case for AC-5 in the myocardium (Hu et al, 2009).…”

Stem Cell–Derived Nodal-Like Cardiomyocytes as a Novel Pharmacologic Tool: Insights from Sinoatrial Node Development and Function

“…This observation most likely explains why disruption of calcium homeostasis also reduces the ability of b-adrenergic agonists to increase I f (Kryukova et al, 2012). Further, the presence of Ca 2+ -activated AC isozymes in SAN also may contribute to the fact that basal cAMP is higher in SAN than elsewhere in the heart Vinogradova et al, 2006;Kryukova et al, 2012). This characteristic of SAN cells is itself important since it provides a means by which cholinergic agonists reduce the spontaneous rate, even in the absence of prestimulation by adrenergic agonists (DiFrancesco et al, 1989).…”

“…Thus, greater Ca 2+ influx might not only increase the depolarizing Na/Ca exchange current but also activate AC1/8, thus increasing cAMP and, through it, I f . This observation most likely explains why disruption of calcium homeostasis also reduces the ability of b-adrenergic agonists to increase I f (Kryukova et al, 2012). Further, the presence of Ca 2+ -activated AC isozymes in SAN also may contribute to the fact that basal cAMP is higher in SAN than elsewhere in the heart Vinogradova et al, 2006;Kryukova et al, 2012).…”

The past, present, and future of pacemaker therapies

“…In vitro experiments showed that AC1 increased baseline cAMP levels, positively shifted the activation V 1/2 of overexpressed HCN2, and increased spontaneous beating in neonatal myocytes overexpressing HCN2. 32 In a subsequent in vivo study, an AC1-carrying adenovirus was injected into the LBB of AV-blocked dogs and showed robust pacemaker activity, including baseline beating rates of ~60 bpm, low dependence on electronic back-up pacing (<2%), and >95% of the beats originating from the injected area. 33 Mechanistically, the AC1-based approach appears to stimulate both I f -dependent and I findependent pacemaker function.…”

“…In these experiments, coexpression of AC1 with HCN2-R/E still resulted in a significant increase in beating rates without affecting kinetics of I f . 32 9…”