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Review
. 2023 Jan 28;12(3):436.
doi: 10.3390/cells12030436.

A-Kinase Anchoring Proteins in Cardiac Myocytes and Their Roles in Regulating Calcium Cycling

Hariharan Subramanian  1   2 , Viacheslav O Nikolaev  1   2
Affiliations
Review

A-Kinase Anchoring Proteins in Cardiac Myocytes and Their Roles in Regulating Calcium Cycling

Hariharan Subramanian et al. Cells. .

Abstract

The rate of calcium cycling and calcium transient amplitude are critical determinants for the efficient contraction and relaxation of the heart. Calcium-handling proteins in the cardiac myocyte are altered in heart failure, and restoring the proper function of those proteins is an effective potential therapeutic strategy. The calcium-handling proteins or their regulators are phosphorylated by a cAMP-dependent kinase (PKA), and thereby their activity is regulated. A-Kinase Anchoring Proteins (AKAPs) play a seminal role in orchestrating PKA and cAMP regulators in calcium handling and contractile machinery. This cAMP/PKA orchestration is crucial for the increased force and rate of contraction and relaxation of the heart in response to fight-or-flight. Knockout models and the few available preclinical models proved that the efficient targeting of AKAPs offers potential therapies tailor-made for improving defective calcium cycling. In this review, we highlight important studies that identified AKAPs and their regulatory roles in cardiac myocyte calcium cycling in health and disease.

Keywords: A-kinase anchoring protein; Calcium cycling; Phospholamban; Protein Kinase A; Ryanodine receptor; SERCA2a; cAMP signaling; calcium channel.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Calcium cycling in cardiac myocytes: depolarizing calcium currents via Cav1.2 induce CICR from SR via RyR2. This increase in cytosolic calcium increases the force of myofilament contraction. For relaxation, most of the calcium is taken back to the SR by SERCA2a, and a significant portion exits via NCX. The calcium-handling proteins Cav1.2, RyR2, and PLN are regulated by AKAP-bound PKA after β-adrenergic receptor (β1 and β2) stimulation. Different AKAPs regulating the calcium-handling proteins are mentioned. Though AKAPs bind multiple proteins, only the binding partners that play a role in calcium cycling are listed. Illustrations in Figure 1 are created with BioRender.com.
Figure 2
Figure 2
Dysregulation of calcium cycling in heart failure: During heart failure, calcium cycling is affected due to the loss of T-tubules and reduced expression/activity of SERCA2a. RyR2 is hyperphosphorylated leading to increased calcium sparks. Illustrations in Figure 2 are created with BioRender.com.
See this image and copyright information in PMC

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