GLP-1 regulates the POMC neurons of the arcuate nucleus both directly and indirectly via presynaptic action

2020 ◽  
Author(s):  
Zoltán Péterfi ◽  
Anett Szilvásy-Szabó ◽  
Erzsébet Farkas ◽  
Yvette Ruska ◽  
Charles Pyke ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Firing Rate ◽  
G Protein ◽  
Arcuate Nucleus ◽  
Male Mice ◽  
Excitatory Effect ◽  
Axon Terminals ◽  
Postsynaptic Currents ◽  
Electrophysiological Studies ◽  
Anorexigenic Effect

GLP-1 exerts its anorexigenic effect at least partly via the POMC neurons of the arcuate nucleus (ARC). These neurons are known to express GLP-1 receptor (GLP-1R). To determine whether in addition to its direct effect, GLP-1 also modulates, how neuronal inputs can regulate the POMC neurons by acting on presynaptic terminals, ultrastructural and electrophysiological studies were performed on tissues of adult male mice. GLP-1R-immunoreactivity was associated with the cell membrane of POMC neurons and with axon terminals forming synapses on these cells. The GLP-1 analog Exendin 4 (Ex4) markedly increased the firing rate of all examined POMC neurons and depolarized these cells. These effects of Ex4 were prevented by intracellular administration of the G-protein blocker GDP-β-S. Ex4 also influenced the miniature and evoked postsynaptic currents (PSCs) of POMC neurons. Ex4 increased the frequency of miniature excitatory PSCs and the amplitude of the evoked excitatory PSCs in half of the POMC neurons. Ex4 increased the frequency of miniature inhibitory PSCs and the amplitudes of the evoked inhibitory PSCs in one-third of neurons. These effects of Ex4 were not influenced by intracellular GDP-β-S, indicating that GLP-1-signaling directly stimulates a population of axon terminals innervating the POMC neurons. The different Ex4 responsiveness of their mPSCs indicates the heterogeneity of the POMC neurons of the ARC. In summary, our data demonstrate that in addition to its direct excitatory effect on the POMC neurons, GLP-1-signaling also facilitates the presynaptic input of these cells by acting on presynaptically localized GLP-1R.

scholarly journals Anorexigenic effect of cholecystokinin is lost but that of CART (Cocaine and Amphetamine Regulated Transcript) peptide is preserved in monosodium glutamate obese mice

2009 ◽  
pp. 717-723 ◽  
Author(s):  
B Železná ◽  
J Maixnerová ◽  
R Matyšková ◽  
R Haugvicová ◽  
D Blokešová ◽  
...  
Keyword(s):  
Food Intake ◽  
Arcuate Nucleus ◽  
Monosodium Glutamate ◽  
Central Administration ◽  
Obese Mice ◽  
Male Mice ◽  
Short Term ◽  
Leptin Signaling ◽  
Cart Peptide ◽  
Anorexigenic Effect

Monosodium glutamate (MSG) treatment of neonatal mice results in a selective damage to the arcuate nucleus (ARC) and development of obesity with increased adiposity at sustained body weight in the adulthood. Feeding pattern of the MSG obese mice is unusual. Our previous results showed that after 24-h fasting, MSG mice consumed negligible amount of food in several hours and therefore, it was impossible to register the effect of peptides attenuating food intake such as cholecystokinin (CCK) or cocaine- and amphetamine-regulated transcript (CART) peptide. To overcome this problem, two findings were used: firstly, orexigenic effect of neuropeptide Y (NPY) was attenuated both by CCK or CART peptide in lean fed mice and secondly, orexigenic effect of NPY was preserved in fed rats with MSG obesity. In this study, short-term food intake in fed lean and MSG obese C57BL/6 male mice was measured after simultaneous central administration of orexigenic NPY with either CART peptide or peripherally administered CCK. Anorexigenic action of exogenous CART peptide was preserved in MSG obese mice. On the other hand, satiety effect of exogenous CCK was completely lost in MSG obese mice. In conclusion, effective leptin signaling in ARC is necessary for satiety effect of CCK.

scholarly journals Central role of G protein Gαi2 and Gαi2+ vomeronasal neurons in balancing territorial and infant-directed aggression of male mice

2019 ◽  
Vol 116 (11) ◽  
pp. 5135-5143 ◽  
Author(s):  
Anne-Charlotte Trouillet ◽  
Matthieu Keller ◽  
Jan Weiss ◽  
Trese Leinders-Zufall ◽  
Lutz Birnbaumer ◽  
...  
Keyword(s):  
G Protein ◽  
Sensory Neurons ◽  
Neural Activity ◽  
Parental Behavior ◽  
Vomeronasal Organ ◽  
Male Infant ◽  
Lateral Septum ◽  
Male Mice ◽  
Protein Subunit ◽  
Α Subunit

Aggression is controlled by the olfactory system in many animal species. In male mice, territorial and infant-directed aggression are tightly regulated by the vomeronasal organ (VNO), but how diverse subsets of sensory neurons convey pheromonal information to limbic centers is not yet known. Here, we employ genetic strategies to show that mouse vomeronasal sensory neurons expressing the G protein subunit Gαi2 regulate male–male and infant-directed aggression through distinct circuit mechanisms. Conditional ablation of Gαi2 enhances male–male aggression and increases neural activity in the medial amygdala (MeA), bed nucleus of the stria terminalis, and lateral septum. By contrast, conditional Gαi2 ablation causes reduced infant-directed aggression and decreased activity in MeA neurons during male–infant interactions. Strikingly, these mice also display enhanced parental behavior and elevated neural activity in the medial preoptic area, whereas sexual behavior remains normal. These results identify Gαi2 as the primary G protein α-subunit mediating the detection of volatile chemosignals in the apical layer of the VNO, and they show that Gαi2+ VSNs and the brain circuits activated by these neurons play a central role in orchestrating and balancing territorial and infant-directed aggression of male mice through bidirectional activation and inhibition of different targets in the limbic system.

scholarly journals Membrane and luminal proteins reach the apicoplast by different trafficking pathways in the malaria parasite Plasmodium falciparum

2017 ◽  
Author(s):  
Rahul Chaudhari ◽  
Vishakha Dey ◽  
Aishwarya Narayan ◽  
Shobhona Sharma ◽  
Swati Patankar
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Membrane ◽  
Membrane Protein ◽  
Host Cell ◽  
G Protein ◽  
Secretory Pathway ◽  
Protein Targeting ◽  
Acyl Carrier Protein ◽  
Secretory Proteins ◽  
Host Cell Membrane

The secretory pathway in Plasmodium falciparum has evolved to transport proteins to the host cell membrane and to an endosymbiotic organelle, the apicoplast. The latter can occur via the ER or the ER-Golgi route. Here, we study these three routes using proteins Erythrocyte Membrane Protein-1 (PfEMP1), Acyl Carrier Protein (ACP) and glutathione peroxidase-like thioredoxin peroxidase (PfTPxGl) and inhibitors of vesicular transport. As expected, the G protein dependent vesicular fusion inhibitor AlF4- and microtubule destabilizing drug vinblastine block the trafficking of PfEMP-1, a protein secreted to the host cell membrane. However, while both PfTPxGl and ACP are targeted to the apicoplast, only ACP trafficking remains unaffected by these treatments. This implies that G-protein dependent vesicles do not play a role in classical apicoplast protein targeting. Unlike the soluble protein ACP, we show that PfTPxGl is localized to the outermost membrane of the apicoplast. Thus, the parasite apicoplast acquires proteins via two different pathways: first, the vesicular trafficking pathway appears to handle not only secretory proteins, but an apicoplast membrane protein, PfTPxGl. Second, trafficking of apicoplast luminal proteins appear to be independent of G-protein coupled vesicles.

scholarly journals Membrane and luminal proteins reach the apicoplast by different trafficking pathways in the malaria parasite Plasmodium falciparum

2017 ◽  
Author(s):  
Rahul Chaudhari ◽  
Vishakha Dey ◽  
Aishwarya Narayan ◽  
Shobhona Sharma ◽  
Swati Patankar
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Membrane ◽  
Membrane Protein ◽  
Host Cell ◽  
G Protein ◽  
Secretory Pathway ◽  
Protein Targeting ◽  
Acyl Carrier Protein ◽  
Secretory Proteins ◽  
Host Cell Membrane

The secretory pathway in Plasmodium falciparum has evolved to transport proteins to the host cell membrane and to an endosymbiotic organelle, the apicoplast. The latter can occur via the ER or the ER-Golgi route. Here, we study these three routes using proteins Erythrocyte Membrane Protein-1 (PfEMP1), Acyl Carrier Protein (ACP) and glutathione peroxidase-like thioredoxin peroxidase (PfTPxGl) and inhibitors of vesicular transport. As expected, the G protein dependent vesicular fusion inhibitor AlF4- and microtubule destabilizing drug vinblastine block the trafficking of PfEMP-1, a protein secreted to the host cell membrane. However, while both PfTPxGl and ACP are targeted to the apicoplast, only ACP trafficking remains unaffected by these treatments. This implies that G-protein dependent vesicles do not play a role in classical apicoplast protein targeting. Unlike the soluble protein ACP, we show that PfTPxGl is localized to the outermost membrane of the apicoplast. Thus, the parasite apicoplast acquires proteins via two different pathways: first, the vesicular trafficking pathway appears to handle not only secretory proteins, but an apicoplast membrane protein, PfTPxGl. Second, trafficking of apicoplast luminal proteins appear to be independent of G-protein coupled vesicles.

Impaired parasympathetic heart rate control in mice with a reduction of functional G protein βγ-subunits

2002 ◽  
Vol 282 (2) ◽  
pp. H445-H456 ◽  
Author(s):  
Josef Gehrmann ◽  
Michael Meister ◽  
Colin T. Maguire ◽  
Donna C. Martins ◽  
Peter E. Hammer ◽  
...  
Keyword(s):  
Heart Rate ◽  
Heart Rate Variability ◽  
Transgenic Mice ◽  
G Protein ◽  
Rate Control ◽  
Sinus Node ◽  
Physiological Role ◽  
Heart Rate Control ◽  
Electrophysiological Studies

Acetylcholine released on parasympathetic stimulation slows heart rate through activation of muscarinic receptors on the sinus nodal cells and subsequent opening of the atrial muscarinic potassium channel (KACh). KACh is directly activated by G protein βγ-subunits. To elucidate the physiological role of Gβγ for the regulation of heart rate and electrophysiological function in vivo, we created transgenic mice with a reduced amount of membrane-bound Gβ protein by overexpressing nonprenylated Gγ2-subunits in their hearts using the α-myosin heavy chain promoter. At baseline and after muscarinic stimulation with carbachol, heart rate and heart rate variability were determined with electrocardiogram telemetry in conscious mice and in vivo intracardiac electrophysiological studies in anesthetized mice. Reduction of the amount of functional Gβγ protein by >50% caused a pronounced blunting of the carbachol-induced bradycardia as well as the increases in time- and frequency-domain indexes of heart rate variability and baroreflex sensitivity that were observed in wild types. In addition, sinus node recovery time and inducibility of atrial arrhythmias were reduced in transgenic mice. Our data demonstrate in vivo that Gβγ plays a crucial role for parasympathetic heart rate control, sinus node automaticity, and atrial arrhythmia vulnerability.

Mechanisms Underlying Type I mGluR-Induced Activation of Lobster Gastric Mill Neurons

2006 ◽  
Vol 96 (6) ◽  
pp. 3378-3388 ◽  
Author(s):  
Rafael Levi ◽  
Allen I. Selverston
Keyword(s):  
G Protein ◽  
Calcium Release ◽  
Metabotropic Glutamate Receptor ◽  
Cyclopiazonic Acid ◽  
Stomatogastric Ganglion ◽  
Type I ◽  
Gastric Mill ◽  
Concentration Increase ◽  
Cellular Mechanisms ◽  
Excitatory Effect

In addition to ionotropic effects, glutamate and acetylcholine have metabotropic modulatory effects on many neurons. Here we show that in the stomatogastric ganglion of the lobster, glutamate, one of the main ionotropic neurotransmitters, modulates the excitability of gastric mill neurons. The neurons in this well-studied system produce rhythmic output to a subset of lobster foregut muscles. Recently, metabotropic glutamate receptor (mGluR) agonists were suggested as modulators of the rhythmic output, in addition to the previously described muscarinic modulation by acetylcholine. However, the cellular mechanisms responsible for these effects on the pattern are not known. Using intracellular recording methods and calcium imaging, we show that glutamate has an excitatory effect on specific neurons in the stomatogastric ganglion, which is mediated by mGluRs. Responses to the application of mGluR type I agonists are transient oscillations in the system, probably arising from network interactions. We show that the excitatory effect is sensitive to phospholipase-C and IP3 and is G-protein dependent. The G-protein dependency was demonstrated by GDPβS and GTPγS injection into identified neurons. The depolarizations and oscillations were accompanied by an increase of intracellular Ca2+ levels and correlated Ca2+ oscillations. By using cyclopiazonic acid, an endoreticular Ca2+ uptake inhibitor, we show that some internal calcium release may augment the response, but is not crucial for its production. Interestingly, although Ca2+ concentration increase is typically associated with the phosphoinositide pathway, in the lobster, the Ca2+ concentration increase—either voltage dependent or independent—cannot account for the observed depolarization.

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