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Adenylyl cyclases 5 and 6 underlie PIP 3 ‐dependent regulation
Author(s) -
Reddy Gopireddy Raghavender,
Subramanian Hariharan,
Birk Alexandra,
Milde Markus,
Nikolaev Viacheslav O.,
Bünemann Moritz
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-268466
Subject(s) - adenylyl cyclase , microbiology and biotechnology , second messenger system , phosphatase , biology , signal transduction , rgs2 , g protein , endocrinology , medicine , phosphorylation , gtpase activating protein
Many different neurotransmitters and hormones control intracellular signaling by regulating the production of the second messenger cAMP. The function of the broadly expressed adenylyl cyclases (ACs) 5 and 6 is regulated by either stimulatory or inhibitory G proteins. By analyzing a well‐known rebound stimulation phenomenon after withdrawal of G i protein in atrial myocytes, we discovered that AC5 and ‐6 are tightly regulated by the second messenger PIP 3 . By monitoring cAMP levels in real time by means of Förster resonance energy transfer (FRET)‐based biosensors, we reproduced the rebound stimulation in a heterologous expression system specifically for AC5 or ‐6. Strikingly, this cAMP rebound stimulation was completely blocked by the PI3K inhibitor wortmannin, both in atrial myocytes and in transfected human embryonic kidney cells. Similar effects were observed by heterologous expression of the PIP3 phosphatase and tensin homolog (PTEN). However, general kinase inhibitors or inhibitors of Akt had no effect, suggesting a PIP 3 ‐dependent mechanism. These findings demonstrate the existence of a novel general pathway for regulation of AC5 and ‐6 activity via PIP3 that leads to pronounced alterations of cytosolic cAMP levels.—Reddy, G. R., Subramanian, H., Birk, A., Milde, M., Nikolaev, V. O., Bünemann, M. Adenylyl cyclases 5 and 6 underlie PIP 3 ‐dependent regulation. FASEB J. 29, 3458‐3471 (2015). www.fasebj.org