“A-kinase” regulator runs amok to provide a paradigm shift in cAMP signaling

Holz, George G.; Chepurny, Oleg G.; Leech, Colin A.

doi:10.1074/jbc.h119.007622

Cited by 5 publications

(4 citation statements)

References 3 publications

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“…This has been proposed, but not tested in the context of P-Rex1-Rac1 mediated GSIS. 11 Furthermore, it may be likely that activation of specific trimeric G proteins via noncanonical mechanism(s) might promote P-Rex1-Rac1 axis leading to GSIS. As proposed recently, 1 such mechanisms might include nonreceptormediated functional activation of individual subunits of trimeric G proteins, such as post-translational carboxyl methylation of specific G γ -subunits and/or histidine phosphorylation of the G βsubunits leading to the activation of the putative trimeric G proteins that couples downstream signaling proteins, such as Phosphatidyl inositol-3-kinase (PI3-kinase) for the activation of P-Rex-1-Rac1 signaling pathway culminating in GSIS.…”

mentioning

confidence: 78%

“…Recent investigations have uncovered novel noncanonical regulation of P-Rex1, which is mediated via binding of the regulatory subunit of protein kinase A (i.e., PKA-Riα) to P-Rex1 leading to activation of its GEF function. This has been proposed, but not tested in the context of P-Rex1-Rac1 mediated GSIS . Furthermore, it may be likely that activation of specific trimeric G proteins via noncanonical mechanism(s) might promote P-Rex1-Rac1 axis leading to GSIS.…”

mentioning

confidence: 99%

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Multiple Guanine Nucleotide Exchange Factors Mediate Glucose-Induced Rac1 Activation and Insulin Secretion: Is It Precise Regulatory Control or a Case of Two Peas from the Same Pod?

Kowluru

2021

ACS Pharmacol. Transl. Sci.

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Glucose-stimulated insulin secretion involves G protein (Rac1)-mediated cytoskeletal remodeling and vesicular transport and fusion with the plasma membrane. Recent evidence implicates at least three guanine nucleotide exchange factors (GEFs), namely, Tiam1, Vav2, and P-Rex1, in glucose-induced activation of Rac1 and insulin secretion. This Viewpoint highlights potential mechanisms underlying Tiam1/Vav2/P-Rex1 sensitive Rac1-mediated insulin secretion in the glucose-stimulated β-cell.

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confidence: 78%

mentioning

confidence: 99%

Multiple Guanine Nucleotide Exchange Factors Mediate Glucose-Induced Rac1 Activation and Insulin Secretion: Is It Precise Regulatory Control or a Case of Two Peas from the Same Pod?

Kowluru

2021

ACS Pharmacol. Transl. Sci.

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“…Since at least in vitro, half maximal activation of PKA and Epac2 occur at different cAMP concentrations, the quantity of cAMP could be another way how Epac2-and PKA-specific effect are mediated [113]. To complicate matters even further, contemporary research with advancements in technology [114] keeps identifying additional aspects of what was believed to be a well-understood signaling mechanism, e.g., Holz et al recently showed that the individual subunit isoforms belonging to PKA can act independently from the accepted canonical signaling pathway, elucidating another layer of complexity to the mechanism of cAMP signaling [115]. Whether CICR is mediated via inositol trisphosphate receptors (IP3R) or ryanodine receptors (RYR) is still debatable.…”

Section: The Effect Of Camp On [Ca 2+ ]Icmentioning

confidence: 99%

The Role of cAMP in Beta Cell Stimulus-Secretion and Inter-cellular Coupling

Stožer¹,

Leitgeb²,

Pohorec³

et al. 2021

Preprint

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Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and gastric inhibitory polypeptide, potentiate glucose-stimulated insulin secretion by binding to G protein-coupled receptors, resulting in stimulation of adenylate cyclase and production of the secondary messenger cAMP, which exerts its intracellular effects through activation of protein kinase A or the guanine nucleotide exchange protein 2A. The mo-lecular mechanisms behind these two downstream signaling arms are still not fully elucidated and involve many steps in the stimulus-secretion coupling cascade, ranging from the proximal regula-tion of ion channel activity, to the central Ca2+ signal, and the most distal exocytosis. In addition to modifying intracellular coupling, the effect of cAMP on insulin secretion could also be at least partly explained by the impact on intercellular coupling. In this review, we systematically describe the possible roles of cAMP at these intra- and inter-cellular signaling nodes, keeping in mind the rele-vance for the whole organism and translation to humans.

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“…An added layer of complexity to cAMP signaling is brought by the ability of the type 1 regulatory subunit of PKA (R1α) to directly bind and activate the phosphatidylinositol-3,4,5trisphosphate-dependent Rac exchange factor 1 (P-Rex1) [131,132]. This cAMP-dependent activation of P-Rex1 by R1α is in contrast to the inhibition of P-Rex1 by PKA-mediated phosphorylation [133].…”

Section: A Novel Indirect Effector Of Camp Signalingmentioning

confidence: 99%

New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling

Tomás

Jones

Leech

2020

Journal of Molecular Biology

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“A-kinase” regulator runs amok to provide a paradigm shift in cAMP signaling

Cited by 5 publications

References 3 publications

Multiple Guanine Nucleotide Exchange Factors Mediate Glucose-Induced Rac1 Activation and Insulin Secretion: Is It Precise Regulatory Control or a Case of Two Peas from the Same Pod?

Multiple Guanine Nucleotide Exchange Factors Mediate Glucose-Induced Rac1 Activation and Insulin Secretion: Is It Precise Regulatory Control or a Case of Two Peas from the Same Pod?

The Role of cAMP in Beta Cell Stimulus-Secretion and Inter-cellular Coupling

New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling

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