AUTHOR=Maghsoudi Saeid , Shuaib Rabia , Van Bastelaere Ben , Dakshinamurti Shyamala 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1370506

DOI=10.3389/fphar.2024.1370506

ISSN=1663-9812

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 main four 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 selec�ve ac�vators or inhibitors, making them difficult to dis�nguish experimentally.AC5 and AC6 are highly expressed in the heart and vasculature, as well as spinal cord and brain;AC6 is also abundant in the lungs, kidney, and liver. However, while AC5 and AC6 have similar expression paterns with some redundant func�ons, they have dis�nct physiological roles due to differing regula�on and cAMP signaling compartmenta�on. AC5 is cri�cal in cardiac and vascular func�on; AC6 is a key effector of vasodilatory pathways in vascular myocytes, and is enriched in fetal/neonatal �ssues. Expression of both AC6 and AC5 decreases in heart failure; but AC5 disrup�on is cardio-protec�ve, while overexpression of AC6 rescues heart func�on in cardiac injury. This is a comprehensive review of the complex regula�on of AC5 and AC6 in the cardiovascular system, highligh�ng overexpression and knockout studies as well as transgenic models illumina�ng each enzyme, and focusing on post-transla�onal modifica�ons that regulate their cellular localiza�on and biological func�ons. We also describe pharmacological challenges in the design of isoform-selec�ve ac�vators or inhibitors for AC5 and 6, which may be relevant to developing new therapeu�c approaches for several cardiovascular diseases.