Thus, the expression and localization of PDEs in a cell contributes to the specificity of the cAMP-response following activation. The expression and localization of PDEs within a cell controls the magnitude and duration of cAMP-dependent events, as well as the compartmentalization and intracellular gradients of cAMP ( Baillie, 2009). Phosphodiesterase’s (PDEs) remain the only known route of cAMP degradation. ACs can also be regulated by other intracellular signals, including Ca 2+ and PKC (see Halls and Cooper, 2017 for a detailed review). Subsequently, the Gsα dissociates from the receptor and Gßγ subunits, activating AC and increasing cAMP levels (see Pierce et al., 2002 for a detailed review of this signaling pathway). When a GPCR is activated by its extracellular ligand, it causes a conformational change in the receptor which activates the associated heteromeric G protein complex, consisting of an α, ß and γ subunit. Membrane-bound ACs are stimulated downstream of Gs-specific G protein-coupled receptor (GPCR) activation, while the sAC is insensitive to GPCR-dependent regulation ( Braun and Dods, 1975 Braun et al., 1977 Forte et al., 1983). The characteristics of each isoform are summarized effectively in several reviews ( Taussig and Gilman, 1995 Simonds, 1999 Hanoune and Defer, 2001 Sadana and Dessauer, 2009 Tresguerres et al., 2011 Halls and Cooper, 2017). cAMP orchestrates numerous signal transduction pathways through the activation of several downstream effector proteins, resulting in a wide variety of cellular processes including gene transcription, cell growth and cell differentiation ( Dumont et al., 1989 Sassone-Corsi, 1995 Mayr and Montminy, 2001 Sands and Palmer, 2008 Bacallao and Monje, 2015).ĬAMP is created from ATP through the action of Adenylate cyclases (AC), of which there are nine membrane-bound isoforms (AC 1-9) and one soluble isoform (sASC). Sutherland in 1958 ( Rall and Sutherland, 1958 Sutherland and Rall, 1958), cyclic adenosine monophosphate (cAMP) is well-recognized as an important intracellular secondary messenger molecule that can induce a cascade of events to influence cellular function ( Patra and Brady, 2018). This review will summarize recent research findings that support the mechanisms of cAMP-dependent regulation of Kv7 channels.ĬAMP-Dependent Signaling Regulators of cAMP: G Protein-Coupled Receptorsįirst discovered by Dr. Although cAMP signaling is recognized to regulate Kv7 channels, the precise molecular mechanism behind the cAMP-dependent regulation of Kv7 channels is complex. A role for cAMP in ion channel regulation has been established, and recent findings show that cAMP signaling plays a role in Kv7 channel regulation. Cyclic adenosine monophosphate (cAMP), a well-known intracellular secondary messenger, can activate numerous downstream effector proteins, generating downstream signaling pathways that regulate many functions in cells. Voltage-gated Kv7 potassium channels, encoded by KCNQ genes, have major physiological impacts cardiac myocytes, neurons, epithelial cells, and smooth muscle cells. George’s University of London, London, United Kingdom 2Molecular and Clinical Sciences Institute, St.1Vascular Biology Group, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
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