Usage Information
Citation Information: JCI Insight. 2022;7(22):e162602. https://doi.org/10.1172/jci.insight.162602.
Abstract
Sinoatrial node (SAN) cells are the heart’s primary pacemaker. Their activity is tightly regulated by β-adrenergic receptor (β-AR) signaling. Adenylyl cyclase (AC) is a key enzyme in the β-AR pathway that catalyzes the production of cAMP. There are current gaps in our knowledge regarding the dominant AC isoforms and the specific roles of Ca2+-activated ACs in the SAN. The current study tests the hypothesis that distinct AC isoforms are preferentially expressed in the SAN and compartmentalize within microdomains to orchestrate heart rate regulation during β-AR signaling. In contrast to atrial and ventricular myocytes, SAN cells express a diverse repertoire of ACs, with ACI as the predominant Ca2+-activated isoform. Although ACI-KO (ACI–/–) mice exhibit normal cardiac systolic or diastolic function, they experience SAN dysfunction. Similarly, SAN-specific CRISPR/Cas9-mediated gene silencing of ACI results in sinus node dysfunction. Mechanistically, hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) channels form functional microdomains almost exclusively with ACI, while ryanodine receptor and L-type Ca2+ channels likely compartmentalize with ACI and other AC isoforms. In contrast, there were no significant differences in T-type Ca2+ and Na+ currents at baseline or after β-AR stimulation between WT and ACI–/– SAN cells. Due to its central characteristic feature as a Ca2+-activated isoform, ACI plays a unique role in sustaining the rise of local cAMP and heart rates during β-AR stimulation. The findings provide insights into the critical roles of the Ca2+-activated isoform of AC in sustaining SAN automaticity that is distinct from contractile cardiomyocytes.
Authors
Lu Ren, Phung N. Thai, Raghavender Reddy Gopireddy, Valeriy Timofeyev, Hannah A. Ledford, Ryan L. Woltz, Seojin Park, Jose L. Puglisi, Claudia M. Moreno, Luis Fernando Santana, Alana C. Conti, Michael I. Kotlikoff, Yang Kevin Xiang, Vladimir Yarov-Yarovoy, Manuela Zaccolo, Xiao-Dong Zhang, Ebenezer N. Yamoah, Manuel F. Navedo, Nipavan Chiamvimonvat
Usage data is cumulative from November 2022 through January 2023.
| Usage | JCI | PMC |
|---|---|---|
| Text version | 1,859 | 20 |
| 294 | 11 | |
| Figure | 511 | 0 |
| Supplemental data | 139 | 1 |
| Citation downloads | 42 | 0 |
| Totals | 2,845 | 32 |
| Total Views | 2,877 | |
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.
