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Review
. 2024 Apr 3:15:1370506.
doi: 10.3389/fphar.2024.1370506. eCollection 2024.

Adenylyl cyclase isoforms 5 and 6 in the cardiovascular system: complex regulation and divergent roles

Saeid Maghsoudi  1   2 , Rabia Shuaib  2 , Ben Van Bastelaere  2 , Shyamala Dakshinamurti  1   2   3
Affiliations
Review

Adenylyl cyclase isoforms 5 and 6 in the cardiovascular system: complex regulation and divergent roles

Saeid Maghsoudi et al. Front Pharmacol. .

Abstract

Adenylyl cyclases (ACs) are crucial effector enzymes that transduce divergent signals from upstream receptor pathways and are responsible for catalyzing the conversion of ATP to cAMP. The ten AC isoforms are categorized into four main groups; the class III or calcium-inhibited family of ACs comprises AC5 and AC6. These enzymes are very closely related in structure and have a paucity of selective activators or inhibitors, making it difficult to distinguish them experimentally. AC5 and AC6 are highly expressed in the heart and vasculature, as well as the spinal cord and brain; AC6 is also abundant in the lungs, kidney, and liver. However, while AC5 and AC6 have similar expression patterns with some redundant functions, they have distinct physiological roles due to differing regulation and cAMP signaling compartmentation. AC5 is critical in cardiac and vascular function; AC6 is a key effector of vasodilatory pathways in vascular myocytes and is enriched in fetal/neonatal tissues. Expression of both AC5 and AC6 decreases in heart failure; however, AC5 disruption is cardio-protective, while overexpression of AC6 rescues cardiac function in cardiac injury. This is a comprehensive review of the complex regulation of AC5 and AC6 in the cardiovascular system, highlighting overexpression and knockout studies as well as transgenic models illuminating each enzyme and focusing on post-translational modifications that regulate their cellular localization and biological functions. We also describe pharmacological challenges in the design of isoform-selective activators or inhibitors for AC5 and AC6, which may be relevant to developing new therapeutic approaches for several cardiovascular diseases.

Keywords: G protein-coupled receptors; adenylyl cyclase; cyclic 3′,5′-adenosine monophosphate; drug discovery; heart disease; signal transduction.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

FIGURE 1
FIGURE 1
(A) Schematic structure of transmembrane adenylyl cyclases (TMACs). TMACs contain an intracellular N-terminus, two repetitions of six TM1 and TM2, and two cytoplasmic domains (C1 and C2) further divided into C1a and C2a. C1a–C2a forms the catalytic domain and FSK-binding site. Inhibitor Gαi binds to C1a, whereas activator Gαs binds to C2a. C1b and C2b are regulatory subdomains, and the N-terminus participates in several protein–protein interactions. Some isoforms are glycosylated on extracellular loops 5 or 6. (B) Specific regulation of AC5 and AC6 by various effectors. Both isoforms are fully activated by Gαs and FSK and partially or conditionally activated by Gβγ. AC5 is activated by PKC, whereas AC6 in inhibited by PKC. Both isoforms are inhibited by Ca2+, Gαi, NO, PKA, and P-site inhibitors (P-SI). Green: stimulation, red: inhibition, and dashed line: conditionally.
FIGURE 2
FIGURE 2
Pathophysiological effects of AC5 deletion and AC6 overexpression. AC5 and AC6 behave distinctly when increased or disrupted. While AC5 deletion has come with several beneficial effects for the heart such as prolonged longevity and enhanced LV function, AC6 overexpression improves cardiac cAMP generation and Ca2+ handling, resulting in improved LV function.
FIGURE 3
FIGURE 3
Schematic representation of the localization of AC5 and AC6 signaling within the t-tubule and sarcolemmal membrane. In ventricular myocytes, AC6 is localized to the plasma membrane outside of the t-tubular region, and it interacts only with β1AR signaling-mediated augmentation of the L-type Ca2+ current (ICa,L), while AC5 is localized to the membrane in t-tubular regions, and its function on ICa,L is restrained by cAMP degradation by phosphodiesterases. Adapted from (Timofeyev et al., 2013); image designed using BioRender.
FIGURE 4
FIGURE 4
Tissue-specific expression of AC5 and AC6. Both isoforms are highly expressed in the heart and spinal cord, followed by the brain.
FIGURE 5
FIGURE 5
Schematic illustration of the cAMP difference detector in situ (cADDis) assay. The enzymatic and catalytic domains of the guanine nucleotide exchange factor Epac2 were joined to form circularly permuted green fluorescent protein (cpGFP). The binding and unbinding of the cAMP molecule cause a conformational change in Epac2.
FIGURE 6
FIGURE 6
AC6 undergoes several post-translational modifications (formula image). AC6 is phosphorylated by PKA and PKC at Ser674 (formula image); phosphorylated by PKC at Ser10 and 568 and Thr931 (formula image); S-nitrosylated by NO at C1004 (formula image); Raf1 on Ser603, 608, 744, 746, 750, and 754 (formula image); and glycosylated at N805 and N890 on extracellular loops 5 and 6.
FIGURE 7
FIGURE 7
Depiction of AC5 signaling effects on cellular antioxidant imbalances in AC5WT and AC5KO hearts. When AC5 is disrupted (AC5KO), there is less βAR-stimulated cAMP, which decreases PKA activity. Lack of PKA leads to the activation of the Raf-1/MEK-ERK signaling pathway to increase the expression of MnSOD. This results in attenuation of oxidative stress. MnSOD antioxidant defense is not as present in AC5WT. O• indicates oxidative stress. Adapted from (Chester and Watts, 2007); image designed using BioRender.
FIGURE 8
FIGURE 8
Effects of AC5 and AC6 overexpression or deletion on heart diseases in vivo. WT and transgenic mice subject to heart failure by catecholamine stress. Mice with deletion of AC5 demonstrate beneficial effects, whereas AC6 deletion is deleterious. AC5 transgenic mice have increased catecholamine stress and cardiac fibrosis. AC5 inhibitors rescue this condition, decreasing the progression of heart disease. Dilated cardiomyopathy in WT mice can be recovered by AC6 gene transfer.
FIGURE 9
FIGURE 9
Involvement of AC5-mediated localized cAMP generation in diabetes and extracellular glucose activation of L-type Ca2+ channels and vasoconstriction. The illustration shows how glucose regulates L-type Ca2+ channel activity and vascular reactivity in an AC5-dependent manner. Increases in extracellular glucose can trigger P2YR linked to Gαs signaling through extracellular nucleotide signaling because of transport and metabolism. Because AC5 and CaV1.2 are close in proximity, this cAMP microdomain may stimulate a pool of AKAP150-anchored PKA that is jointly linked to CaV1.2, making it to become more phosphorylated at Ser1928 and increasing channel function. Adapted from (Syed et al., 2019); image designed using BioRender.
FIGURE 10
FIGURE 10
Possible modification sites on the parent compound forskolin molecule, for the design of selective AC5 or AC6 activators. Based on previous studies, any modification on C (1) reduces AC activity. Modifications on C (6) and (7) have the potential to enhance AC5 and AC6 activity.
FIGURE 11
FIGURE 11
Structures of known inhibitors and activators targeting AC5 and AC6 allosteric or catalytic sites. Inhibitors (green) are mainly P-site inhibitors, and activators (red) are forskolin derivatives.
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Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This project is supported by grants from Heart and Stroke Foundation (SD) (HSFC grant # G-23-0034213) and Canadian Institutes of Health Research (SD) (CIHR grant # PJT 175165).

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