Compartmentation of Cyclic Nucleotide Signaling in the Heart

Abstract

Abstract-A current challenge in cellular signaling is to decipher the complex intracellular spatiotemporal organization that any given cell type has developed to discriminate among different external stimuli acting via a common signaling pathway. This obviously applies to cAMP and cGMP signaling in the heart, where these cyclic nucleotides determine the regulation of cardiac function by many hormones and neuromediators. Key Words: cAMP Ⅲ cGMP Ⅲ heart Ⅲ G protein-coupled receptor Ⅲ phosphodiesterase T he cyclic nucleotides cyclic adenosine 3Ј,5Ј-monophosphate (cAMP) and cyclic guanosine 3Ј,5Ј-monophosphate (cGMP) were identified more than 4 decades ago. 1,2 Since then, many studies have appeared on how these 2 second messengers are synthesized or degraded, what makes their level go up or down, what they do to target effectors by either covalent (phosphorylation) or noncovalent (direct binding to proteins, such as ion channels or guanine-nucleotide-exchange factors) mechanisms, and how they affect a countless number of cellular functions. [3][4][5][6] In certain tissues and organs, the cyclic nucleotide pathways have been so fully explored over the years that one can wonder what else is there to be found. This is the case for cAMP in the heart, where it plays a key role in the sympathetic nerve/␤-adrenergic receptor (␤-AR)/adenylyl cyclase (AC)/protein kinase A (PKA) axis that serves to stimulate cardiac rhythm (chronotropy) as well as contractile force (inotropy) and relaxation (lusitropy). 7 Yet, there are a number of questions that have always made us wonder but have only lately begun to receive the attention they deserve: how so many different receptors coupled to cAMP or cGMP signaling pathway manage to achieve specific cellular responses? What is the purpose of the different adenylyl and guanylyl cyclases present in the same cell? Why do Original

In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease

“…3 0 ,5 0 -Cyclic adenosine monophosphate (cAMP) is an ubiquitous intracellular second messenger that, by acting in discrete subcellular microdomains, regulates a plethora of physiological and pathological processes including cardiac function and disease [1][2][3] . This is achieved primarily by cAMPdependent protein kinase (PKA)-mediated phosphorylation of several proteins involved in calcium handling and excitationcontraction coupling such as L-type calcium channels, ryanodine receptors, troponin I and phospholamban (PLN) 4 .…”

Newly Identified NO‐Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function

“…Cyclic nucleotide signaling is highly compartmentalized, mostly through the activity of phosphodiesterases,12 and proper cardiac physiological function relies on the organization, in microdomains, of these intracellular signaling pathways 13, 14. Disruption of the cAMP‐related signaling could be induced, for example, by dysregulation of the cGMP‐inhibited phosphodiesterase 3, which preferentially hydrolyzes cAMP 13, 35.…”

“…In cardiomyocytes, the activity of phosphodiesterases allows the compartmentalization of cyclic nucleotide signaling 12. In specific microdomains, cGMP can modulate cAMP signaling by activation or inhibition of cAMP breakdown by phosphodiesterases 2 and 3, respectively.…”

Revisiting Kadenbach: Electron flux rate through cytochrome c‐oxidase determines the ATP‐inhibitory effect and subsequent production of ROS

“…This type of PDE2A is located in the matrix. Concerning different signaling chains for protein phosphorylations 104 and multiple phosphorylation sites of CytOx 105, 106, and the ‘so far known’ compartmentation of cyclic nucleotide signaling 107 on the other hand, we have to address the question whether all the different cAC actions 108 are maintained by a network of different PDE's in the mitochondria or in the intramembranous space 109.…”