scholarly journals Dopamine Negatively Modulates the NCA Ion Channels in C. elegans

2016 ◽  
Author(s):  
Irini Topalidou ◽  
Kirsten Cooper ◽  
Laura Pereira ◽  
Michael Ailion
Keyword(s):  
Ion Channels ◽  
Dopamine Receptor ◽  
G Protein ◽  
G Proteins ◽  
Function Analysis ◽  
Small Gtpase ◽  
Resting Membrane Potential ◽  
Membrane Excitability ◽  
C Elegans ◽  
Dopamine Signaling

AbstractThe NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels.Author summaryDopamine is a neurotransmitter that acts in the brain by binding seven transmembrane receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins). Neuronal G proteins often function by modulating ion channels that control membrane excitability. Here we identify a molecular cascade downstream of dopamine in the nematode C. elegans that involves activation of the dopamine receptor DOP-3, activation of the G protein GOA-1, and inactivation of the NCA-1 and NCA-2 ion channels. We also identify a G protein-coupled receptor kinase (GRK-2) that inactivates the dopamine receptor DOP-3, thus leading to inactivation of GOA-1 and activation of the NCA channels. Thus, this study connects dopamine signaling to activity of the NCA channels through G protein signaling pathways.

scholarly journals G Proteins and GPCRs in C. elegans Development: A Story of Mutual Infidelity

2018 ◽  
Vol 6 (4) ◽  
pp. 28 ◽  
Author(s):  
Daniel Matúš ◽  
Simone Prömel
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
G Proteins ◽  
Cell Polarity ◽  
Protein Activity ◽  
Independent Manner ◽  
C Elegans ◽  
Downstream Effectors ◽  
Complex Signaling ◽  
G Protein Coupled

Many vital processes during C. elegans development, especially the establishment and maintenance of cell polarity in embryogenesis, are controlled by complex signaling pathways. G protein-coupled receptors (GPCRs), such as the four Frizzled family Wnt receptors, are linchpins in regulating and orchestrating several of these mechanisms. However, despite being GPCRs, which usually couple to G proteins, these receptors do not seem to activate classical heterotrimeric G protein-mediated signaling cascades. The view on signaling during embryogenesis is further complicated by the fact that heterotrimeric G proteins do play essential roles in cell polarity during embryogenesis, but their activity is modulated in a predominantly GPCR-independent manner via G protein regulators such as GEFs GAPs and GDIs. Further, the triggered downstream effectors are not typical. Only very few GPCR-dependent and G protein-mediated signaling pathways have been unambiguously defined in this context. This unusual and highly intriguing concept of separating GPCR function and G-protein activity, which is not restricted to embryogenesis in C. elegans but can also be found in other organisms, allows for essential and multi-faceted ways of regulating cellular communication and response. Although its relevance cannot be debated, its impact is still poorly discussed, and C. elegans is an ideal model to understand the underlying principles.

Ion Channels as G Protein Effectors

Physiology ◽  
1991 ◽  
Vol 6 (4) ◽  
pp. 158-161
Author(s):  
AM Brown
Keyword(s):  
Membrane Potential ◽  
Ion Channels ◽  
Cell Signaling ◽  
G Protein ◽  
G Proteins ◽  
Heterotrimeric G Proteins ◽  
Regulatory Processes ◽  
Functional Implications

Signaling between cells may be accomplished or accompanied by changes in membrane potential. The latter is regulated by ion channels, which are targets for regulatory processes initiated during signaling. Cell signaling frequently involves heterotrimeric G proteins. Evidence that ion channels are G protein effectors and functional implications of such regulation are reviewed.

Ion channel regulation by G proteins

1995 ◽  
Vol 75 (4) ◽  
pp. 865-885 ◽  
Author(s):  
K. Wickman ◽  
D. E. Clapham
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
G Protein ◽  
G Proteins ◽  
Second Messengers ◽  
Channel Activity ◽  
Ion Channel Regulation ◽  
Protein Subunits ◽  
Channel Regulation ◽  
Intracellular Cascades

Ion channels are poised uniquely to initiate, mediate, or regulate such distinct cellular activities as action potential propagation, secretion, and gene transcription. In retrospect, it is not surprising that studies of ion channels have revealed considerable diversities in their primary structures, regulation, and expression. From a functional standpoint, the various mechanisms coopted by cells to regulate channel activity are particularly fascinating. Extracellular ligands, membrane potential, phosphorylation, ions themselves, and diffusible second messengers are all well-established regulators of ion channel activity. Heterotrimeric GTP-binding proteins (G proteins) mediate many of these types of ion channel regulation by stimulating or inhibiting phosphorylation pathways, initiating intracellular cascades leading to elevation of cytosolic Ca2+ or adenosine 3',5'-cyclic monophosphate levels, or by generating various lipid-derived compounds. In some cases, it seems that activated G protein subunits can interact directly with ion channels to elicit regulation. Although there is currently little direct biochemical evidence to support such a mechanism, it is the working hypothesis for the most-studied G protein-regulated ion channels.

scholarly journals Small G Proteins Dexras1 and RHES and Their Role in Pathophysiological Processes

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Ashish Thapliyal ◽  
Rashmi Verma ◽  
Navin Kumar
Keyword(s):  
Ion Channels ◽  
Cell Growth ◽  
G Proteins ◽  
Cell Lines ◽  
Calcium Ion ◽  
Small Gtpase ◽  
Calcium Ion Channels ◽  
Hormonal Release ◽  
Small G Proteins

Dexras1 and RHES, monomeric G proteins, are members of small GTPase family that are involved in modulation of pathophysiological processes. Dexras1 and RHES levels are modulated by hormones and Dexras1 expression undergoes circadian fluctuations. Both these GTPases are capable of modulating calcium ion channels which in turn can potentially modulate neurosecretion/hormonal release. These two GTPases have been reported to prevent the aberrant cell growth and induce apoptosis in cell lines. Present review focuses on role of these two monomeric GTPases and summarizes their role in pathophysiological processes.

scholarly journals 3.6.5.2 Small monomeric GTPases (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Elena Faccenda
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Small Gtpase ◽  
Alpha Subunit ◽  
Heterotrimeric G Proteins ◽  
Guanosine Triphosphate ◽  
Guanosine Diphosphate ◽  
Ras Gtpases ◽  
Small G Proteins

Small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best-known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases.

scholarly journals Homologous and unique G protein alpha subunits in the nematode Caenorhabditis elegans.

1991 ◽  
Vol 2 (2) ◽  
pp. 135-154 ◽  
Author(s):  
M A Lochrie ◽  
J E Mendel ◽  
P W Sternberg ◽  
M I Simon
Keyword(s):  
Amino Acid ◽  
G Protein ◽  
G Proteins ◽  
Amino Acid Sequences ◽  
Alpha Subunit ◽  
Predicted Amino Acid Sequence ◽  
C Elegans ◽  
Alpha Subunits ◽  
G Protein Alpha Subunit ◽  
Protein Alpha Subunit

A cDNA corresponding to a known G protein alpha subunit, the alpha subunit of Go (Go alpha), was isolated and sequenced. The predicted amino acid sequence of C. elegans Go alpha is 80-87% identical to other Go alpha sequences. An mRNA that hybridizes to the C. elegans Go alpha cDNA can be detected on Northern blots. A C. elegans protein that crossreacts with antibovine Go alpha antibody can be detected on immunoblots. A cosmid clone containing the C. elegans Go alpha gene (goa-1) was isolated and mapped to chromosome I. The genomic fragments of three other C. elegans G protein alpha subunit genes (gpa-1, gpa-2, and gpa-3) have been isolated using the polymerase chain reaction. The corresponding cosmid clones were isolated and mapped to disperse locations on chromosome V. The sequences of two of the genes, gpa-1 and gpa-3, were determined. The predicted amino acid sequences of gpa-1 and gpa-3 are only 48% identical to each other. Therefore, they are likely to have distinct functions. In addition they are not homologous enough to G protein alpha subunits in other organisms to be classified. Thus C. elegans has G proteins that are identifiable homologues of mammalian G proteins as well as G proteins that appear to be unique to C. elegans. Study of identifiable G proteins in C. elegans may result in a further understanding of their function in other organisms, whereas study of the novel G proteins may provide an understanding of unique aspects of nematode physiology.

Understanding the Binding Specificity of G-Protein Coupled Receptors toward G-Proteins and Arrestins: Application to the Dopamine Receptor Family

2020 ◽  
Vol 60 (8) ◽  
pp. 3969-3984 ◽  
Author(s):  
A. J. Preto ◽  
Carlos A. V. Barreto ◽  
Salete J. Baptista ◽  
José Guilherme de Almeida ◽  
Agostinho Lemos ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
G Protein ◽  
G Proteins ◽  
Binding Specificity ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled ◽  
Receptor Family

Direct G protein gating of ion channels

1988 ◽  
Vol 254 (3) ◽  
pp. H401-H410 ◽  
Author(s):  
A. M. Brown ◽  
L. Birnbaumer
Keyword(s):  
Ion Channels ◽  
G Protein ◽  
G Proteins ◽  
Second Messengers ◽  
Ionic Channels ◽  
Neurosecretory Cells ◽  
Alpha Subunit ◽  
K Channel ◽  
Human Red Blood Cells ◽  
Ca2 Channels

Guanine nucleotide binding (G) proteins couple a variety of receptors to ionic channels. Until recently the pathway was thought to be indirect via cytoplasmic second messengers; now the heterotrimeric G proteins are known to act directly on K+ and Ca2+ channels. Here we summarize recent developments concerning this widespread mechanism which we call G protein gating of ion channels. A specific pertussis toxin-sensitive G protein called Gk, purified from human red blood cells, activates a unique K+ channel and Gk, or a similar G protein, couples this channel to muscarinic atrial receptors. The alpha-subunit (alpha k) at less than 10 pM mediates the effects, and alpha k also activates K+ channels directly in neurosecretory cells. The G protein stimulatory to adenylyl cyclase, Gs, gates directly through its alpha-subunit, specific Ca2+ channels in heart and skeletal muscle T tubules. Hence, one G protein can have two distinct effectors.

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