Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Adenylyl cyclase isoform 1 contributes to sinoatrial node automaticity via functional microdomains
Lu Ren, … , Manuel F. Navedo, Nipavan Chiamvimonvat
Lu Ren, … , Manuel F. Navedo, Nipavan Chiamvimonvat
Published November 22, 2022
Citation Information: JCI Insight. 2022;7(22):e162602. https://doi.org/10.1172/jci.insight.162602.
View: Text | PDF
Research Article Cardiology

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

  • Text
  • PDF
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

×

Figure 5

ACI–/– SAN cells exhibit an impaired β-AR response of Ca2+ transients (CaTs) with Ca2+ alternans and a blunted response of local Ca2+ release (LCR) to β-AR stimulation.

Options: View larger image (or click on image) Download as PowerPoint

ACI–/– SAN cells exhibit an impaired β-AR response of Ca2+ transients (...
(A) Representative whole-cell CaT traces of SAN cells from WT and ACI–/– mice before and after ISO application. (B–G) Summary data of τrise (B), τdecay (C), percentages of nonfiring duration (D), normalized peak amplitude (E), beating rate (F), and percentage of cells exhibiting nonfiring activity (G). Number of symbols in the bar graphs represents number of cells. n = 19–33 cells from n = 6–7 mice per group. (H) Representative LCR recordings from WT and ACI–/– SAN cells before and after ISO application. (I) Representative 3D reconstructions of Ca2+ sparks in WT SAN cells. (J–M) Summary data of spark rate (spark numbers per AP cycle, normalized per 100 μm) (J), amplitude (K), full width at half maximum (FWHM) (L), and full duration at half maximum (FDHM) (M). Each symbol represents the average of sparks from 1 cell. n = 16–18 cells from n = 6–7 mice per group. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by 2-way ANOVA with repeated measures, followed by Holm-Sidak multiple-comparison post hoc analyses.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts