Adenylyl cyclase isoform 1 contributes to sinoatrial node automaticity via functional microdomains

WITHDRAWN: Caveolar Compartmentalization is Required for Stable Rhythmicity of Sinus Nodal Cells and is Disrupted in Heart Failure

“…This gap is particularly crucial to address because simply altering the function of one or more pacemaker ion currents cannot fully explain the complex SND phenotype observed in both Cav-3-KO and HF mice, characterized by bradycardia, sinus pauses, recurrent development of SAN quiescence, and profound beat-to-beat CL variations. Our findings significantly contribute to the emerging evidence highlighting an additional layer of pacemaker organization, 4,6,29,32 i.e., a tightly coupled, interacting network of molecules involved in pacemaker activity. In the present study, we demonstrated, in both mouse and human SANCs, the pivotal role of caveolae in organizing sarcolemmal electrogenic proteins within a specialized pacemaker signalosome, mediated by their association with Cav-3 scaffolding protein.…”

“…S5) clearly demonstrated the close association of these proteins, with a distinct punctate expression pattern on the surface membrane, likely indicative of caveolae structures as shown previously. 4,10 These data were further corroborated by the presence of complementary caveolin binding motifs identified in the amino acid sequences of mouse and human HCN4, Ca v 1.2, Ca v 1.3, Ca v 3.1 and NCX1 proteins (Fig. S6).…”

“…Caveolin-3 (Cav-3) is the specific and predominant caveolin isoform expressed in muscle 9 and acts as a scaffolding protein by compartmentalizing and concentrating signaling molecules within caveolae. 4,10,11 Moreover, through direct protein-protein interaction, Cav-3 can modulate the biophysical properties of associated ion channels and organize large macromolecular signaling complexes, [12][13][14] contributing to nanodomain-specific regulation of cardiac physiology and pathophysiological remodeling and arrhythmogenesis. 11,[15][16][17] Disruption of caveolar nanodomains and/or downregulation/malfunction of Cav-3 were observed in various pathological conditions that are concomitantly associated with SND, including heart failure (HF), 18 atrial fibrillation, 19 and hypertension.…”

Compartmentalized cAMP signalling and control of cardiac rhythm

“…The overall cAMP levels appear to be three times higher in SAN than in ventricles, despite the concurrent higher activity of PDEs, and this is a result of constitutive AC activity, rather than β-AR hyperactivation [ 85 ]. The calcium-activated AC1 is a crucial source of cAMP in SAN cells, whereas it contributes only relatively marginally to cAMP production in the ventricles [ 23 , 111 ], which can explain the elevated cAMP levels. AC1 is co-localized within caveolae with proteins involved in the generation of cardiac rhythm, including HCN channels underlying the funny current, ryanodine receptors, and CaV channels underlying the L-type calcium current [ 111 ].…”

“…The calcium-activated AC1 is a crucial source of cAMP in SAN cells, whereas it contributes only relatively marginally to cAMP production in the ventricles [ 23 , 111 ], which can explain the elevated cAMP levels. AC1 is co-localized within caveolae with proteins involved in the generation of cardiac rhythm, including HCN channels underlying the funny current, ryanodine receptors, and CaV channels underlying the L-type calcium current [ 111 ]. The calcium-activated nature of AC1 leads to a self-sustaining feedforward loop, where high cAMP activity activates and accelerates cellular calcium handling, which in turn stimulates cAMP formation by the AC1.…”