Developmental expression of G proteins in a migratory population of embryonic neurons

Development ◽  
1994 ◽  
Vol 120 (4) ◽  
pp. 729-742 ◽  
Author(s):  
A.M. Horgan ◽  
M.T. Lagrange ◽  
P.F. Copenhaver
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
G Protein ◽  
G Proteins ◽  
Enteric Neurons ◽  
Developmental Expression ◽  
Heterotrimeric G Proteins ◽  
Aluminium Fluoride ◽  
Related Proteins ◽  
Embryonic Neurons

Directed neuronal migration contributes to the formation of many developing systems, but the molecular mechanisms that control the migratory process are still poorly understood. We have examined the role of heterotrimeric G proteins (guanyl nucleotide binding proteins) in regulating the migratory behavior of embryonic neurons in the enteric nervous system of the moth, Manduca sexta. During the formation of the enteric nervous system, a group of approx. 300 enteric neurons (the EP cells) participate in a precise migratory sequence, during which the undifferentiated cells populate a branching nerve plexus that lies superficially on the visceral musculature. Once migration is complete, the cells then acquire a variety of position-specific neuronal phenotypes. Using affinity-purified antisera against different G protein subtypes, we found no apparent staining for any G protein in the EP cells prior to their migration. Coincident with the onset of migration, however, the EP cells commenced the expression of one particular G protein, Go alpha. The intensity of immunostaining continued to increase as migration progressed, with Go alpha immunoreactivity being detectable in the leading processes of the neurons as well as their somata. The identity of the Go alpha-related proteins was confirmed by protein immunoblot analysis and by comparison with previously described forms of Go alpha from Drosophila. When cultured embryos were treated briefly with aluminium fluoride, a compound known to stimulate the activity of heterotrimeric G proteins, both EP cell migration and process outgrowth were inhibited. The effects of aluminium fluoride were potentiated by alpha toxin, a pore-forming compound that by itself caused no significant perturbations of migration. In preliminary experiments, intracellular injections of the non-hydrolyzable nucleotide GTP gamma-S also inhibited the migration of individual EP cells, supporting the hypothesis that G proteins play a key role in the control of neuronal motility in this system. In addition, once migration was complete, the expression of Go alpha-related proteins in the EP cells underwent a subsequent phase of regulation, so that only certain phenotypic classes among the differentiated EP cells retained detectable levels of Go alpha immunoreactivity. Thus Go may perform multiple functions within the same population of migratory neurons in the course of embryonic development.

scholarly journals G protein-coupled receptor trafficking and signaling: new insights into the enteric nervous system

2019 ◽  
Vol 316 (4) ◽  
pp. G446-G452 ◽  
Author(s):  
Simona E. Carbone ◽  
Nicholas A. Veldhuis ◽  
Arisbel B. Gondin ◽  
Daniel P. Poole
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Intestinal Inflammation ◽  
Receptor Expression ◽  
Enteric Neurons ◽  
Future Research ◽  
Detailed Knowledge ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are essential for the neurogenic control of gastrointestinal (GI) function and are important and emerging therapeutic targets in the gut. Detailed knowledge of both the distribution and functional expression of GPCRs in the enteric nervous system (ENS) is critical toward advancing our understanding of how these receptors contribute to GI function during physiological and pathophysiological states. Equally important, but less well defined, is the complex relationship between receptor expression, ligand binding, signaling, and trafficking within enteric neurons. Neuronal GPCRs are internalized following exposure to agonists and under pathological conditions, such as intestinal inflammation. However, the relationship between the intracellular distribution of GPCRs and their signaling outputs in this setting remains a “black box”. This review will briefly summarize current knowledge of agonist-evoked GPCR trafficking and location-specific signaling in the ENS and identifies key areas where future research could be focused. Greater understanding of the cellular and molecular mechanisms involved in regulating GPCR signaling in the ENS will provide new insights into GI function and may open novel avenues for therapeutic targeting of GPCRs for the treatment of digestive disorders.

scholarly journals II. Regulation of neuropeptide receptors in enteric neurons

1998 ◽  
Vol 274 (5) ◽  
pp. G792-G796
Author(s):  
Karen McConalogue ◽  
Nigel W. Bunnett
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Target Cell ◽  
Biological Effects ◽  
G Protein Coupled Receptors ◽  
Enteric Neurons ◽  
Heterotrimeric G Proteins ◽  
High Affinity ◽  
Neuropeptide Receptors ◽  
G Protein Coupled

Neuropeptides exert their diverse biological effects by interacting with G protein-coupled receptors (GPCRs). In this review we address the question, What regulates the ability of a target cell, in particular a neuron, to respond to a neuropeptide? Available evidence from studies of many GPCRs in reconstituted systems and transfected cell lines indicates that much of this regulation occurs at the level of the receptor and serves to alter the capacity of the receptor to bind ligands with high affinity and to couple to heterotrimeric G proteins. Although some of the knowledge gained from these studies is applicable to the regulation of neuropeptide receptors on neurons, at present there are far more questions than answers.

Developmental expression of heterotrimeric G proteins in the nervous system ofManduca sexta

1995 ◽  
Vol 26 (4) ◽  
pp. 461-484 ◽  
Author(s):  
P. F. Copenhaver ◽  
A. M. Horgan ◽  
D. C. Nichols ◽  
M. A. Rasmussen
Keyword(s):  
Nervous System ◽  
G Proteins ◽  
Developmental Expression ◽  
Heterotrimeric G Proteins

scholarly journals Every Detail Matters. That Is, How the Interaction between Gα Proteins and Membrane Affects Their Function

Membranes ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 222
Author(s):  
Agnieszka Polit ◽  
Paweł Mystek ◽  
Ewa Błasiak
Keyword(s):  
Signal Transduction ◽  
G Protein ◽  
G Proteins ◽  
Lipid Membranes ◽  
Signaling Proteins ◽  
Heterotrimeric G Proteins ◽  
Membrane Attachment ◽  
The Individual ◽  
Multicellular Organisms ◽  
G Protein Coupled

In highly organized multicellular organisms such as humans, the functions of an individual cell are dependent on signal transduction through G protein-coupled receptors (GPCRs) and subsequently heterotrimeric G proteins. As most of the elements belonging to the signal transduction system are bound to lipid membranes, researchers are showing increasing interest in studying the accompanying protein–lipid interactions, which have been demonstrated to not only provide the environment but also regulate proper and efficient signal transduction. The mode of interaction between the cell membrane and G proteins is well known. Despite this, the recognition mechanisms at the molecular level and how the individual G protein-membrane attachment signals are interrelated in the process of the complex control of membrane targeting of G proteins remain unelucidated. This review focuses on the mechanisms by which mammalian Gα subunits of G proteins interact with lipids and the factors responsible for the specificity of membrane association. We summarize recent data on how these signaling proteins are precisely targeted to a specific site in the membrane region by introducing well-defined modifications as well as through the presence of polybasic regions within these proteins and interactions with other components of the heterocomplex.

scholarly journals Signaling from G Protein-coupled Receptors to ERK5/Big MAPK 1 Involves Gαqand Gα12/13Families of Heterotrimeric G Proteins

2000 ◽  
Vol 275 (28) ◽  
pp. 21730-21736 ◽  
Author(s):  
Shigetomo Fukuhara ◽  
Maria Julia Marinissen ◽  
Mario Chiariello ◽  
J. Silvio Gutkind
Keyword(s):  
G Protein ◽  
G Proteins ◽  
G Protein Coupled Receptors ◽  
Heterotrimeric G Proteins ◽  
G Protein Coupled

scholarly journals Physiological Regulation of G Protein-Linked Signaling

1999 ◽  
Vol 79 (4) ◽  
pp. 1373-1430 ◽  
Author(s):  
Andrew J. Morris ◽  
Craig C. Malbon
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Chemokine Receptors ◽  
Transcriptional Control ◽  
Heterotrimeric G Proteins ◽  
Protein Prenylation ◽  
Physiological Control ◽  
Physiological Regulation ◽  
Surface Receptors ◽  
Genes Encoding

Heterotrimeric G proteins in vertebrates constitute a family molecular switches that transduce the activation of a populous group of cell-surface receptors to a group of diverse effector units. The receptors include the photopigments such as rhodopsin and prominent families such as the adrenergic, muscarinic acetylcholine, and chemokine receptors involved in regulating a broad spectrum of responses in humans. Signals from receptors are sensed by heterotrimeric G proteins and transduced to effectors such as adenylyl cyclases, phospholipases, and various ion channels. Physiological regulation of G protein-linked receptors allows for integration of signals that directly or indirectly effect the signaling from receptor→G protein→effector(s). Steroid hormones can regulate signaling via transcriptional control of the activities of the genes encoding members of G protein-linked pathways. Posttranscriptional mechanisms are under physiological control, altering the stability of preexisting mRNA and affording an additional level for regulation. Protein phosphorylation, protein prenylation, and proteolysis constitute major posttranslational mechanisms employed in the physiological regulation of G protein-linked signaling. Drawing upon mechanisms at all three levels, physiological regulation permits integration of demands placed on G protein-linked signaling.

scholarly journals Heterotrimeric G-Proteins Are Indispensable for FLT3-ITD autophosphorylation and Oncogenic Function

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2712-2712
Author(s):  
Maike Rehage ◽  
Susanne Wingert ◽  
Nadine Haetscher ◽  
Sabrina Bothur ◽  
Hubert Serve ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
G Protein ◽  
G Proteins ◽  
B Cell Lymphoma ◽  
Physical Interaction ◽  
Heterotrimeric G Proteins ◽  
Leukemic Transformation ◽  
Hematopoietic Stem ◽  
Oncogenic Function

Abstract Heterotrimeric G-proteins transmit signals of G-protein coupled receptors and regulate many basic cellular functions. However, their role in normal and malignant hematopoietic stem cells remains obscure. Activating mutations in the heterotrimeric G-protein Gaq were found in various cancers and its expression is enhanced in diffuse large B-cell lymphoma and T-ALL. Our previous data suggested the involvement of heterotrimeric G-proteins in Flt3-ITD-mediated leukemic transformation. FMS-like tyrosine kinase 3 with internal tandem duplication (FLT3-ITD) is a frequent oncoprotein in acute myeloid leukemia causing constitutive active STAT5 signaling. Here, we investigated a novel role of Gaq in Flt3-ITD-induced leukemic transformation. We could show that Gaq is indispensable for aberrant FLT3-ITD activation and oncogenic function as Gaq activity is necessary to maintain the autophosphorylation of FLT3-ITD. Gaq abrogation resulted in diminished cell proliferation and colony formation as well as delayed leukemogenesis in vivo of Flt3-ITD leukemic cells. Importantly, the growth inhibition could be rescued by addition of IL3 and did not occur in the presence of FLT3 ligand-activated FLT3 wildtype receptor, demonstrating the specificity of Gaq requirement for FLT3-ITD oncogenic signaling. Interestingly, co-immunoprecipitations revealed a direct physical interaction between FLT3-ITD and Gaq which did not require phosphorylation of the receptor tyrosine kinase. Hence, FLT3-ITD hyperphosphorylation seems to be rather a consequence of the interaction than a prerequisite. Flt3-ITD-induced transformation of murine hematopoietic stem/progenitor cells (HSPCs) strictly depended on the presence of Gaq, and the ablation of Gaq/11 in transplanted Flt3-ITD-transduced HSPCs from conditional Gaq/11 double knock-out mice delayed leukemic burden. These findings of an unexpected, yet critical, role of Gaq place the molecule as an important target for antileukemic strategies. Disclosures No relevant conflicts of interest to declare.

In ovo transplantation of enteric nervous system precursors from vagal to sacral neural crest results in extensive hindgut colonisation

Development ◽  
2002 ◽  
Vol 129 (12) ◽  
pp. 2785-2796 ◽  
Author(s):  
Alan J. Burns ◽  
Jean-Marie M. Delalande ◽  
Nicole M. Le Douarin
Keyword(s):  
Nervous System ◽  
Neural Crest ◽  
Enteric Nervous System ◽  
Enteric Neurons ◽  
In Ovo ◽  
Neuronal Marker ◽  
Sacral Region ◽  
Enteric Ganglia ◽  
Migration Front ◽  
Sacral Neural Crest

The enteric nervous system (ENS) is derived from vagal and sacral neural crest cells (NCC). Within the embryonic avian gut, vagal NCC migrate in a rostrocaudal direction to form the majority of neurons and glia along the entire length of the gastrointestinal tract, whereas sacral NCC migrate in an opposing caudorostral direction, initially forming the nerve of Remak, and contribute a smaller number of ENS cells primarily to the distal hindgut. In this study, we have investigated the ability of vagal NCC, transplanted to the sacral region of the neuraxis, to colonise the chick hindgut and form the ENS in an experimentally generated hypoganglionic hindgut in ovo model. Results showed that when the vagal NC was transplanted into the sacral region of the neuraxis, vagal-derived ENS precursors immediately migrated away from the neural tube along characteristic pathways, with numerous cells colonising the gut mesenchyme by embryonic day (E) 4. By E7, the colorectum was extensively colonised by transplanted vagal NCC and the migration front had advanced caudorostrally to the level of the umbilicus. By E10, the stage at which sacral NCC begin to colonise the hindgut in large numbers, myenteric and submucosal plexuses in the hindgut almost entirely composed of transplanted vagal NCC, while the migration front had progressed into the pre-umbilical intestine, midway between the stomach and umbilicus. Immunohistochemical staining with the pan-neuronal marker, ANNA-1, revealed that the transplanted vagal NCC differentiated into enteric neurons, and whole-mount staining with NADPH-diaphorase showed that myenteric and submucosal ganglia formed interconnecting plexuses, similar to control animals. Furthermore, using an anti-RET antibody, widespread immunostaining was observed throughout the ENS, within a subpopulation of sacral NC-derived ENS precursors, and in the majority of transplanted vagal-to-sacral NCC. Our results demonstrate that: (1) a cell autonomous difference exists between the migration/signalling mechanisms used by sacral and vagal NCC, as transplanted vagal cells migrated along pathways normally followed by sacral cells, but did so in much larger numbers, earlier in development; (2) vagal NCC transplanted into the sacral neuraxis extensively colonised the hindgut, migrated in a caudorostral direction, differentiated into neuronal phenotypes, and formed enteric plexuses; (3) RET immunostaining occurred in vagal crest-derived ENS cells, the nerve of Remak and a subpopulation of sacral NCC within hindgut enteric ganglia.

Multiple mechanisms of receptor-G protein signaling specificity

1995 ◽  
Vol 269 (2) ◽  
pp. F141-F158 ◽  
Author(s):  
J. R. Raymond
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Linear Models ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Heterotrimeric G Proteins ◽  
Cellular Functions ◽  
Signaling Specificity ◽  
Intracellular Signals ◽  
Specific Manner

The hormone-receptor-G protein complex transduces extracellular information into intracellular signals that ultimately regulate cellular functions in a highly specific manner. There are hundreds of receptor types that transduce signals through a relatively limited repertoire of heterotrimeric G proteins. Linear models of signaling specificity that require specific and highly selective coupling of hormone to receptor to G protein have proven inadequate to explain how highly particular signals are funneled through the G protein "bottleneck." Recent studies have uncovered a plethora of mechanisms that contribute to signaling specificity. This review focuses on the mechanisms that contribute to specificity in the interactions of receptors with G proteins.

Endothelin-B receptors activate Gα13

1999 ◽  
Vol 276 (4) ◽  
pp. C930-C937 ◽  
Author(s):  
Kenichiro Kitamura ◽  
Naoki Shiraishi ◽  
William D. Singer ◽  
Mary E. Handlogten ◽  
Kimio Tomita ◽  
...  
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Guanine Nucleotides ◽  
Heterotrimeric G Proteins ◽  
Human Embryonic Kidney ◽  
Cellular Effects ◽  
293 Cells ◽  
Specific Antagonist ◽  
Α Chain ◽  
Endothelin B

Endothelin (ET) receptors activate heterotrimeric G proteins that are members of the Gi, Gq, and Gs families but may also activate members of other families such as Gα12/13. Gα13 has multiple complex cellular effects that are similar to those of ET. We studied the ability of ET receptors to activate Gα13 using an assay for G protein α-chain activation that is based on the fact that an activated (GTP-bound) α-chain is resistant to trypsinization compared with an inactive (GDP-bound) α-chain. Nonhydrolyzable guanine nucleotides and AlMgF protected Gα13 from degradation by trypsin. In membranes from human embryonic kidney 293 cells that coexpress ETB receptors and α13, ET-3 and 5′-guanylylimidodiphosphate [Gpp(NH)p] increased the protection of α13 compared with Gpp(NH)p alone. The specificity of ETBreceptor-α13 coupling was documented by showing that β2receptors and isoproterenol or ETAreceptors and ET-1 did not activate α13 and that a specific antagonist for ETB receptors blocked ET-3-dependent activation of α13.

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