Physiological Roles of Mammalian Transmembrane Adenylyl Cyclase Isoforms

2021 ◽  
Author(s):  
Katrina F. Ostrom ◽  
Justin E. LaVigne ◽  
Tarsis F. Brust ◽  
Roland Seifert ◽  
Carmen W Dessauer ◽  
...  
Keyword(s):  
Physiological Responses ◽  
Expression Patterns ◽  
G Protein Coupled Receptors ◽  
Camp Signaling ◽  
Physiological Effects ◽  
Adenylyl Cyclases ◽  
Vast Array ◽  
Redundant Functions ◽  
G Protein Coupled ◽  
Made In

Adenylyl cyclases (ACs) catalyze the conversion of ATP to the ubiquitous second messenger cAMP. Mammals possess nine isoforms of transmembrane ACs, dubbed AC1-9, that serve as major effector enzymes of G protein-coupled receptors. The transmembrane ACs display varying expression patterns across tissues, giving potential for them having a wide array of physiologic roles. Cells express multiple AC isoforms, implying that ACs have redundant functions. Furthermore, all transmembrane ACs are activated by Gαs so it was long assumed that all ACs are activated by Gαs-coupled GPCRs. AC isoforms partition to different microdomains of the plasma membrane and form prearranged signaling complexes with specific GPCRs that contribute to cAMP signaling compartments. This compartmentation allows for a diversity of cellular and physiological responses by enabling unique signaling events to be triggered by different pools of cAMP. Isoform specific pharmacological activators or inhibitors are lacking for most ACs, making knockdown and overexpression the primary tools for examining the physiological roles of a given isoform. Much progress has been made in understanding the physiological effects mediated through individual transmembrane ACs. GPCR-AC-cAMP signaling pathways play significant roles in regulating functions of every cell and tissue, so understanding each AC isoform's role holds potential for uncovering new approaches for treating a vast array of pathophysiological conditions.

scholarly journals Imaging of persistent cAMP signaling by internalized G protein-coupled receptors

2010 ◽  
Vol 45 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Davide Calebiro ◽  
Viacheslav O Nikolaev ◽  
Martin J Lohse
Keyword(s):  
G Protein ◽  
Intracellular Signaling ◽  
Current Model ◽  
Living Cells ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Optical Methods ◽  
Camp Signaling ◽  
Gpcr Signaling ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. They mediate the effects of several endogenous cues and serve as important pharmacological targets. Although many biochemical events involved in GPCR signaling have been characterized in great detail, little is known about their spatiotemporal dynamics in living cells. The recent advent of optical methods based on fluorescent resonance energy transfer allows, for the first time, to directly monitor GPCR signaling in living cells. Utilizing these methods, it has been recently possible to show that the receptors for two protein/peptide hormones, the TSH and the parathyroid hormone, continue signaling to cAMP after their internalization into endosomes. This type of intracellular signaling is persistent and apparently triggers specific cellular outcomes. Here, we review these recent data and explain the optical methods used for such studies. Based on these findings, we propose a revision of the current model of the GPCR–cAMP signaling pathway to accommodate receptor signaling at endosomes.

Fluorescence Observation of Single-Cell cAMP Signaling by G Protein-Coupled Receptors

2018 ◽  
Vol 29 (1) ◽  
pp. 53-60 ◽  
Author(s):  
Dongmei Zhang ◽  
Giuma E. Hadhoud ◽  
Karen Helm ◽  
Deborah A. Roess ◽  
B. George Barisas
Keyword(s):  
Single Cell ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Camp Signaling ◽  
G Protein Coupled ◽  
Fluorescence Observation

scholarly journals The G-protein-coupled receptors GPR3 and GPR12 are involved in cAMP signaling and maintenance of meiotic arrest in rodent oocytes

2005 ◽  
Vol 287 (2) ◽  
pp. 249-261 ◽  
Author(s):  
Mary Hinckley ◽  
Sergio Vaccari ◽  
Kathleen Horner ◽  
Ruby Chen ◽  
Marco Conti
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Camp Signaling ◽  
Meiotic Arrest ◽  
G Protein Coupled

scholarly journals A high-throughput CRISPR interference screen for dissecting functional regulators of GPCR/cAMP signaling

2020 ◽  
Author(s):  
Khairunnisa Mentari Semesta ◽  
Ruilin Tian ◽  
Martin Kampmann ◽  
Mark von Zastrow ◽  
Nikoleta G. Tsvetanova
Keyword(s):  
G Protein ◽  
High Throughput ◽  
G Protein Coupled Receptors ◽  
Camp Signaling ◽  
Proper Function ◽  
Sensory Stimuli ◽  
Crispr Interference ◽  
Screening Platform ◽  
G Protein Coupled ◽  
Proof Of Principle

AbstractG protein-coupled receptors (GPCRs) allow cells to respond to chemical and sensory stimuli through generation of second messengers, such as cyclic AMP (cAMP), which in turn mediate a myriad of processes, including cell survival, proliferation, and differentiation. In order to gain deeper insights into the complex biology and physiology of these key cellular pathways, it is critical to be able to globally map the molecular factors that shape cascade function. Yet, to this date, efforts to systematically identify regulators of GPCR/cAMP signaling have been lacking. Here, we combined genome-wide screening based on CRISPR interference with a novel sortable transcriptional reporter that provides robust readout for cAMP signaling, and carried out a functional screen for regulators of the pathway. Due to the sortable nature of the platform, we were able to assay regulators with strong and weaker phenotypes by analyzing sgRNA distribution among three fractions with distinct reporter expression. We identified 45 regulators with strong and 50 regulators with weaker phenotypes not previously known to be involved in cAMP signaling. In follow-up experiments, we validated the functional effects of seven newly discovered mediators (NUP93, PRIM1, RUVBL1, PKMYT1, TP53, SF3A2, and HRAS), and showed that they control distinct steps of the pathway. Thus, our study provides proof of principle that the screening platform can be applied successfully to identify bona fide regulators of GPCR/second messenger cascades in an unbiased and high-throughput manner, and illuminates the remarkable functional diversity among GPCR regulators.Author summaryCells sense and respond to changes in their surrounding environment through G protein-coupled receptors (GPCRs) and their associated cascades. The proper function of these pathways is essential to human physiology, and GPCRs have become a prime target for drug development for a range of human diseases. Therefore, it is of utmost importance to be able to map how these pathways operate to enable cells to fine-tune their responsiveness. Here, we describe a screening approach that we have devised to systematically identify regulators of GPCR function. We have developed a sortable reporter system and coupled that with silencing of genes across the entire human genome in order to uncover a range of novel mediators of GPCR activity. We characterize a few of these new regulators and show that they function at different steps of the cascade. Therefore, this study serves as proof of principle for the new screening platform. We envision that the approach can be used to dissect additional dimensions of GPCR function, including regulators of drug-specific responses, functional characterization of receptor features, and identification of novel drugs, and thus advance a genome-scale understanding of these critical pathways.

scholarly journals Roles of G Protein-Coupled Receptors (GPCRs) in Gastrointestinal Cancers: Focus on Sphingosine 1-Shosphate Receptors, Angiotensin II Receptors, and Estrogen-Related GPCRs

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2988
Author(s):  
Zhen Zeng ◽  
Chunxiang Ma ◽  
Kexin Chen ◽  
Mingshan Jiang ◽  
Reshma Vasu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Angiotensin Ii Receptors ◽  
Biological Processes ◽  
Substantial Evidence ◽  
Sphingosine 1 Phosphate ◽  
Gi Cancers ◽  
G Protein Coupled ◽  
Made In

It is well established that gastrointestinal (GI) cancers are common and devastating diseases around the world. Despite the significant progress that has been made in the treatment of GI cancers, the mortality rates remain high, indicating a real need to explore the complex pathogenesis and develop more effective therapeutics for GI cancers. G protein-coupled receptors (GPCRs) are critical signaling molecules involved in various biological processes including cell growth, proliferation, and death, as well as immune responses and inflammation regulation. Substantial evidence has demonstrated crucial roles of GPCRs in the development of GI cancers, which provided an impetus for further research regarding the pathophysiological mechanisms and drug discovery of GI cancers. In this review, we mainly discuss the roles of sphingosine 1-phosphate receptors (S1PRs), angiotensin II receptors, estrogen-related GPCRs, and some other important GPCRs in the development of colorectal, gastric, and esophageal cancer, and explore the potential of GPCRs as therapeutic targets.

Role and Function of Adenosine and its Receptors in Inflammation, Neuroinflammation, IBS, Autoimmune Inflammatory Disorders, Rheumatoid Arthritis and Psoriasis

2019 ◽  
Vol 25 (26) ◽  
pp. 2875-2891 ◽  
Author(s):  
Ashok K. Shakya ◽  
Rajashri R. Naik ◽  
Ihab M. ALMASRI ◽  
Avneet Kaur
Keyword(s):  
Rheumatoid Arthritis ◽  
Adenosine Receptors ◽  
G Protein Coupled Receptors ◽  
Physiological Effects ◽  
Xanthine Derivatives ◽  
Organ Systems ◽  
New Chemical Entities ◽  
And Function ◽  
G Protein Coupled ◽  
Role And Function

The physiological effects of endogenous adenosine on various organ systems are very complex and numerous which are elicited upon activation of any of the four G-protein-coupled receptors (GPCRs) denoted as A1, A2A, A2B and A3 adenosine receptors (ARs). Several fused heterocyclic and non-xanthine derivatives are reported as a possible target for these receptors due to physiological problems and lack of selectivity of xanthine derivatives. In the present review, we have discussed the development of various new chemical entities as a target for these receptors. In addition, compounds acting on adenosine receptors can be utilized in treating diseases like inflammation, neuroinflammation, autoimmune and related diseases.

scholarly journals cAMP Signaling Regulates DNA Demethylation by Augmenting the Intracellular Labile Ferrous Iron Pool

2017 ◽  
Author(s):  
Vladimir Camarena ◽  
David W. Sant ◽  
Tyler C. Huff ◽  
Sushmita Mustafi ◽  
Ryan K. Muir ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Phosphodiesterase Inhibitors ◽  
Cell Types ◽  
Dna Demethylation ◽  
G Protein Coupled Receptors ◽  
Camp Signaling ◽  
Multiple Cell ◽  
Iron Pool ◽  
Transcriptomic Changes ◽  
G Protein Coupled

AbstractIt is widely accepted that cAMP regulates gene transcription principally by activating the protein kinase A (PKA)-targeted transcription factors. Here, we show that cAMP enhances the generation of 5-hydroxymethylcytosine (5hmC) in multiple cell types. 5hmC is converted from 5-methylcytosine (5mC) by Tet methylcytosine dioxygenases, for which Fe(II) is an essential cofactor. The promotion of 5hmC was mediated by a prompt increase of the intracellular labile Fe(II) pool (LIP). cAMP enhanced the acidification of endosomes for Fe(II) release to the LIP likely through RapGEF2. The effect of cAMP on Fe(II) and 5hmC was confirmed by adenylate cyclase activators, phosphodiesterase inhibitors, and most notably by stimulation of G protein-coupled receptors (GPCR). The transcriptomic changes caused by cAMP occurred in concert with 5hmC elevation in differentially transcribed genes. Collectively, these data show a previously unrecognized regulation of gene transcription by GPCR-cAMP signaling through augmentation of the intracellular labile Fe(II) pool and DNA demethylation.

scholarly journals Seeing cells smell: Dynamic optical measurements of Ca2+ and cAMP signaling from Olfactory Receptors transiently expressed in HEK293TN cells

2019 ◽  
Author(s):  
A Pietraszewska-Bogiel ◽  
L van Weeren ◽  
J Goedhart
Keyword(s):  
G Protein ◽  
Therapeutic Potential ◽  
Olfactory Receptors ◽  
Functional Expression ◽  
G Protein Coupled Receptors ◽  
Optical Measurements ◽  
Camp Signaling ◽  
Kinetic Measurements ◽  
Fluorescent Biosensors ◽  
G Protein Coupled

ABSTRACTOlfactory receptors (ORs) constitute the largest family of G-protein coupled receptors. They are responsible for the perception of odor (olfaction) and also play important roles in other biological processes, including regulation of cell proliferation. Their increasing diagnostic and therapeutic potential, especially for cancer research, requests the ongoing development of methodologies that would allow their robust functional expression in non-olfactory cells, and dynamic analysis of their signaling pathways. To enable realtime detection of OR activity, we use single cell imaging with genetically encoded fluorescent biosensors, Yellow Cameleon or EPAC, which are routinely used for kinetic measurements of Ca2+ or cAMP signaling downstream of various G-protein coupled receptors. We demonstrate that the co-expression of Lucy-Rho tagged variants of ORs together with an accessory protein, RTP1s, in HEK293TN cells is sufficient to detect the activity of a panel of ORs. Using this methodology, we were able to detect both Ca2+ and cAMP signaling downstream of twelve ORs within 2 minutes from the application of odorant.

scholarly journals Endothelins and hypoxia-inducible factor in cancer

2007 ◽  
Vol 14 (2) ◽  
pp. 233-244 ◽  
Author(s):  
M J Grimshaw
Keyword(s):  
Hypoxia Inducible Factor ◽  
Tumour Microenvironment ◽  
G Protein Coupled Receptors ◽  
Vascular Endothelial ◽  
Small Peptides ◽  
Tumour Type ◽  
Endothelin System ◽  
Endothelial Growth Factor ◽  
G Protein Coupled ◽  
Made In

The endothelin system is a family of three similar small peptides, two G-protein-coupled receptors and two proteinases. Endothelins have several physiological roles, notably in embryonic differentiation and vascular homeostasis. Numerous types of tumour express endothelins and their regulation is often aberrant when compared with the normal tissue from which the tumour arose. However, endothelin expression is tumour-type specific, and in some instances, expression of individual members of the endothelin system will be upregulated, while in other tumour types, they may be downregulated. Endothelins have numerous potential roles in tumours including modulating angiogenesis, inducing mitogenesis and invasion of tumour cells, and protecting cells from apoptosis. Expression of endothelins is controlled by the tumour microenvironment, whilst the endothelins themselves modify that environment; a case in point is that hypoxia stimulates endothelin expression via hypoxia-inducible factor (HIF)-1, while endothelins stabilise HIF-1 leading to expression of, for instance, vascular endothelial growth factor. This review highlights the potential roles of endothelins in various cancers and describes the pre-clinical and clinical progress that has been made in several tumour types – notably prostate, ovary, melanoma and breast cancer. The interactions between the endothelin network and HIF-1 are highlighted.

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