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Journal ArticleDOI

Organization and Ca2+ Regulation of Adenylyl Cyclases in cAMP Microdomains

01 Jul 2007-Physiological Reviews (American Physiological Society)-Vol. 87, Iss: 3, pp 965-1010
TL;DR: The regulation of many of the ACs by the ubiquitous second messenger Ca(2+) provides an overarching mechanism for integrating the activities of these two major signaling systems, and cAMP will exhibit distinct kinetics in discrete cellular domains.
Abstract: The adenylyl cyclases are variously regulated by G protein subunits, a number of serine/threonine and tyrosine protein kinases, and Ca2+. In some physiological situations, this regulation can be re...
Citations
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Journal ArticleDOI
TL;DR: This Review focuses on emerging principles of c-di-GMP signalling using selected systems in different bacteria as examples.
Abstract: On the stage of bacterial signal transduction and regulation, bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) has long played the part of Sleeping Beauty. c-di-GMP was first described in 1987, but only recently was it recognized that the enzymes that 'make and break' it are not only ubiquitous in the bacterial world, but are found in many species in huge numbers. As a key player in the decision between the motile planktonic and sedentary biofilm-associated bacterial 'lifestyles', c-di-GMP binds to an unprecedented range of effector components and controls diverse targets, including transcription, the activities of enzymes and larger cellular structures. This Review focuses on emerging principles of c-di-GMP signalling using selected systems in different bacteria as examples.

1,337 citations


Cites background from "Organization and Ca2+ Regulation of..."

  • ...Moreover, in eukaryotic cells, adenylate cyclases have been shown to function in cAMP microdomain...

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Journal ArticleDOI
TL;DR: Evidence is examined that forms the basis of this coupled-clock system concept in cardiac SANCs, where G protein-coupled receptors signaling creates pacemaker flexibility, ie, effects changes in the rhythmic action potential firing rate, by impacting on these very same factors that regulate robust basal coupled- clock system function.
Abstract: Ion channels on the surface membrane of sinoatrial nodal pacemaker cells (SANCs) are the proximal cause of an action potential. Each individual channel type has been thoroughly characterized under voltage clamp, and the ensemble of the ion channel currents reconstructed in silico generates rhythmic action potentials. Thus, this ensemble can be envisioned as a surface "membrane clock" (M clock). Localized subsarcolemmal Ca(2+) releases are generated by the sarcoplasmic reticulum via ryanodine receptors during late diastolic depolarization and are referred to as an intracellular "Ca(2+) clock," because their spontaneous occurrence is periodic during voltage clamp or in detergent-permeabilized SANCs, and in silico as well. In spontaneously firing SANCs, the M and Ca(2+) clocks do not operate in isolation but work together via numerous interactions modulated by membrane voltage, subsarcolemmal Ca(2+), and protein kinase A and CaMKII-dependent protein phosphorylation. Through these interactions, the 2 subsystem clocks become mutually entrained to form a robust, stable, coupled-clock system that drives normal cardiac pacemaker cell automaticity. G protein-coupled receptors signaling creates pacemaker flexibility, ie, effects changes in the rhythmic action potential firing rate, by impacting on these very same factors that regulate robust basal coupled-clock system function. This review examines evidence that forms the basis of this coupled-clock system concept in cardiac SANCs.

553 citations

Journal ArticleDOI
TL;DR: The role of Caveolae/caveolin in cardiac and pulmonary pathophysiology, pharmacologic implications of caveolar localization of signaling molecules, and the possibility that caveolae might serve as a therapeutic target are reviewed.
Abstract: Caveolae, a subset of membrane (lipid) rafts, are flask-like invaginations of the plasma membrane that contain caveolin proteins, which serve as organizing centers for cellular signal transduction. Caveolins (-1, -2, and -3) have cytoplasmic N and C termini, palmitolylation sites, and a scaffolding domain that facilitates interaction and organization of signaling molecules so as to help provide coordinated and efficient signal transduction. Such signaling components include upstream entities (e.g., G protein-coupled receptors (GPCRs), receptor tyrosine kinases, and steroid hormone receptors) and downstream components (e.g., heterotrimeric and low-molecular-weight G proteins, effector enzymes, and ion channels). Diseases associated with aberrant signaling may result in altered localization or expression of signaling proteins in caveolae. Caveolin-knockout mice have numerous abnormalities, some of which may reflect the impact of total body knockout throughout the life span. This review provides a general overview of caveolins and caveolae, signaling molecules that localize to caveolae, the role of caveolae/caveolin in cardiac and pulmonary pathophysiology, pharmacologic implications of caveolar localization of signaling molecules, and the possibility that caveolae might serve as a therapeutic target.

428 citations

Journal ArticleDOI
TL;DR: Genes for these important regulatory enzymes are linked to schizophrenia, stroke and asthma, thus indicating the therapeutic potential that selective inhibitors could have as anti-inflammatory, anti-depressant and cognitive enhancer agents.

403 citations

Journal ArticleDOI
TL;DR: The latest on AC knockout and overexpression studies are explored to better understand the roles of G protein regulation of ACs in the brain, olfactory bulb, and heart.
Abstract: Cyclic AMP is a universal second messenger, produced by a family of adenylyl cyclase (AC) enzymes. The last three decades have brought a wealth of new information about the regulation of cyclic AMP production by ACs. Nine hormone-sensitive, membrane-bound AC isoforms have been identified in addition to a tenth isoform that lacks membrane spans and more closely resembles the cyanobacterial AC enzymes. New model systems for purifying and characterizing the catalytic domains of AC have led to the crystal structure of these domains and the mapping of numerous interaction sites. However, big hurdles remain in unraveling the roles of individual AC isoforms and their regulation in physiological systems. In this review we explore the latest on AC knockout and overexpression studies to better understand the roles of G protein regulation of ACs in the brain, olfactory bulb, and heart.

322 citations

References
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Journal ArticleDOI
TL;DR: It is now becoming clear that lipid micro-environments on the cell surface — known as lipid rafts — also take part in this process of signalling transduction, where protein–protein interactions result in the activation of signalling cascades.
Abstract: Signal transduction is initiated by complex protein-protein interactions between ligands, receptors and kinases, to name only a few. It is now becoming clear that lipid micro-environments on the cell surface -- known as lipid rafts -- also take part in this process. Lipid rafts containing a given set of proteins can change their size and composition in response to intra- or extracellular stimuli. This favours specific protein-protein interactions, resulting in the activation of signalling cascades.

6,080 citations


"Organization and Ca2+ Regulation of..." refers background in this paper

  • ...Lipid rafts are areas of plasma membrane heterogeneity, characterized by high concentrations of cholesterol and sphingolipids, which are distinct from the glycerophospholipid-rich (nonraft) plasma membrane domains (350)....

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Journal ArticleDOI
TL;DR: The key electrophysiological features of I(CRAC) and other store-operated Ca(2+) currents and how they are regulated are described, and recent advances that have shed insight into the molecular mechanisms involved in this ubiquitous and vital Ca( 2+) entry pathway are considered.
Abstract: In electrically nonexcitable cells, Ca2+ influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and prolifera...

2,248 citations

Journal ArticleDOI
TL;DR: This article reviews many of the more important aspects about the structure, cellular localization, and regulation of each family of phosphodiesterases and places particular emphasis on new information obtained in the last few years about how differential expression andregulation of individual phosphodiesters relate to their function(s) in the body.
Abstract: In the last few years there has been a veritable explosion of knowledge about cyclic nucleotide phosphodiesterases. In particular, the accumulating data showing that there are a large number of different phosphodiesterase isozymes have triggered an equally large increase in interest about these enzymes. At least seven different gene families of cyclic nucleotide phosphodiesterase are currently known to exist in mammalian tissues. Most families contain several distinct genes, and many of these genes are expressed in different tissues as functionally unique alternative splice variants. This article reviews many of the more important aspects about the structure, cellular localization, and regulation of each family of phosphodiesterases. Particular emphasis is placed on new information obtained in the last few years about how differential expression and regulation of individual phosphodiesterase isozymes relate to their function(s) in the body. A substantial discussion of the currently accepted nomenclature is also included. Finally, a brief discussion is included about how the differences among distinct phosphodiesterase isozymes are beginning to be used as the basis for developing therapeutic agents.

1,796 citations


"Organization and Ca2+ Regulation of..." refers background in this paper

  • ...Since the identification of the Ca(2) -stimulated PDE1 in 1970 (77, 201), 10 further members of this superfamily have been cloned and characterized (27, 88, 97, 113, 133, 149, 187, 240, 251, 427)....

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Journal ArticleDOI
06 Mar 1980-Nature
TL;DR: Cell membrane receptors for hormones and neurotransmitters form oligomeric complexes with GTP-regulatory proteins and inhibit the latter from reacting with G TP, and this theory may apply generally to membrane signal transduction involving surface receptors.
Abstract: Cell membrane receptors for hormones and neurotransmitters form oligomeric complexes with GTP-regulatory proteins and inhibit the latter from reacting with GTP. Hormones and neurotransmitters act by releasing the inhibitory constraints imposed by the receptors, thus allowing the GTP-regulatory proteins to interact with and control the activity of enzymes such as adenylate cyclase. This theory may apply generally to membrane signal transduction involving surface receptors.

1,686 citations

Journal ArticleDOI
14 Nov 2003-Cell
TL;DR: There has been considerable recent interest in the possibility that the plasma membrane contains lipid "rafts," microdomains enriched in cholesterol and sphingolipids, and it seems that a definitive proof of raft existence has yet to be obtained.

1,415 citations


"Organization and Ca2+ Regulation of..." refers background in this paper

  • ...It is important to acknowledge that both of these preparations at best may be frozen snapshots in the lives of what are dynamic assemblies (217, 241) or at worst, preparation-induced assemblies (16, 269)....

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  • ...The notion that signaling elements can be concentrated in such domains and so rendered more efficient in their interaction has been enthusiastically embraced in many areas of signaling (302), but it would be reasonable to acknowledge that there is far from a universal consensus on what may be occurring (16, 269)....

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