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Updated: Aug 17, 2025
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Methods for the Isolation, Culture, and Functional Characterization of Sinoatrial Node Myocytes from Adult Mice
Published on: October 23, 2016
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Adenylyl cyclase isoform 1 contributes to sinoatrial node automaticity via functional microdomains
Lu Ren1,2, Phung N Thai1,3, Raghavender Reddy Gopireddy4
1Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.
JCI Insight
|December 12, 2022
Summary
The predominant Ca2+-activated adenylyl cyclase isoform 1 (ACI) is crucial for sinoatrial node (SAN) function. Loss of ACI impairs heart rate regulation, highlighting its unique role in pacemaker cells.
Area of Science:
- Cardiology
- Molecular Biology
- Electrophysiology
Background:
- Sinoatrial node (SAN) cells pace the heart, with activity regulated by β-adrenergic receptor (β-AR) signaling.
- Adenylyl cyclase (AC) enzymes produce cAMP, a key second messenger in the β-AR pathway.
- Specific AC isoforms and their roles in SAN microdomains remain incompletely understood.
Purpose of the Study:
- To investigate the expression and function of AC isoforms in SAN cells.
- To determine the role of Ca2+-activated ACs, particularly ACI, in SAN pacemaking.
- To elucidate the compartmentalization of ACs within SAN cell microdomains.
Main Methods:
- Comparative analysis of AC isoform expression in SAN, atrial, and ventricular myocytes.
- Generation and analysis of ACI knockout (ACI-KO) mice.
- SAN-specific gene silencing of ACI using CRISPR/Cas9.
- Electrophysiological recordings of ion channel function in SAN cells.
Main Results:
- SAN cells express a diverse range of AC isoforms, with ACI being the predominant Ca2+-activated isoform.
- ACI-KO mice and ACI-silenced SAN cells exhibit significant sinus node dysfunction.
- ACI forms functional microdomains with HCN4 channels, essential for β-AR-mediated heart rate increases.
- Other Ca2+ channels and receptors interact with ACI and other AC isoforms.
Conclusions:
- ACI plays a unique and critical role in regulating SAN automaticity and heart rate.
- Compartmentalization of ACI within specific microdomains is vital for cAMP signaling in SAN cells.
- These findings differentiate SAN pacemaking mechanisms from those in contractile cardiomyocytes.
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