Interrogating the Spatiotemporal Landscape of Neuromodulatory GPCR Signaling by Real-Time Imaging of cAMP in Intact Neurons and Circuits

Muntean, Brian S.; Zucca, Stefano; MacMullen, Courtney; Dao, Maria; Johnston, Caitlin; Iwamoto, Hideki; Blakely, Randy D.; Davis, Ronald L.; Martemyanov, Kirill A.

doi:10.1016/j.celrep.2018.07.031

Cited by 32 publications

(46 citation statements)

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“…Consistently, we found that the activation of DMS-GPe iMSNs reduced ethanol-containing reward-seeking as much as the devalued state (10E10S presentation before the test) in the extinction tests. Recently developed CAMPER (cyclic adenosine monophosphate cAMP encoded reporter) strategy using different changes of cAMP level between G␣i-coupled A 1 R and G␣olfcoupled A 2A R may simultaneously determine the adenosine signaling-dependent dynamics of iMSNs and dMSNs in rewardseeking behaviors (Muntean et al, 2018). In the nucleus accumbens (NAc), however, it is not clear the distinction between dMSNs and iMSNs (Kupchik et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Indirect Medium Spiny Neurons in the Dorsomedial Striatum Regulate Ethanol-Containing Conditioned Reward Seeking

et al. 2019

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Adenosine 2A receptor (A 2A R)-containing indirect medium spiny neurons (iMSNs) in the dorsomedial striatum (DMS) contribute to reward-seeking behaviors. However, those roles for ethanol-seeking behaviors remain unknown. To investigate ethanol-seeking behaviors, we used an ethanol-containing reward (10% ethanol and 10% sucrose solution; 10E10S). Upon conditioning with 10E10S, mice that initially only preferred 10% sucrose, not 10E10S, showed a stronger preference for 10E10S. Then, we investigated whether the manipulation of the DMS-external globus pallidus (GPe) iMSNs circuit alters the ethanol-containing reward (10E10S) seeking behaviors using the combination of pharmacologic and optogenetic approaches. DMS A 2A R activation dampened operant conditioning-induced ethanolcontaining reward, whereas A 2A R antagonist abolished the effects of the A 2A R agonist and restored ethanol-containing reward-seeking. Moreover, pre-ethanol exposure potentiated the A 2A R-dependent reward-seeking. Interestingly, mice exhibiting ethanol-containing reward-seeking showed the reduction of the DMS iMSNs activity, suggesting that disinhibiting iMSNs decreases reward-seeking behaviors. In addition, we found that A 2A R activation reversed iMSNs neural activity in the DMS. Similarly, optogenetic stimulation of the DMS-GPe iMSNs reduced ethanol-containing reward-seeking, whereas optogenetic inhibition of the DMS-GPe iMSNs reversed this change. Together, our study demonstrates that DMS A 2A R and iMSNs regulate ethanol-containing reward-seeking behaviors.

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Section: Discussionmentioning

confidence: 99%

Indirect Medium Spiny Neurons in the Dorsomedial Striatum Regulate Ethanol-Containing Conditioned Reward Seeking

et al. 2019

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“…Many labs are addressing system bias issues and are beginning to evaluate signalling in more relevant cellular models, including primary neurons (Jamshidi et al, 2015;Ho et al, 2018;Ehrlich et al, 2019). A major limiting factor is the inability to evaluate signalling bias in vivo, although advances are ongoing, such as measuring cAMP signalling in mice (Muntean et al, 2018).…”

Section: G-protein Biased Kappa Opioid Receptor Agonistsmentioning

confidence: 99%

Strategies for DevelopingκOpioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects

Paton

Atigari

Kaska

et al. 2020

J Pharmacol Exp Ther

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“…cAMPER and GCaMP6 reporter mice. We used the following Cre drivers to express fluorescent biosensors for calcium (GCaMP6s; Gt(ROSA)26Sor tm96(CAG-GCaMP6s)Hze ) [34]or cAMP (C57BL/6-Gt(ROSA)26Sor tm1(CAG-ECFP*/Rapgef3/Venus*)Kama /J) (cAMPER, The Jackson Laboratory, strain #032205) [35] directly and specifically in  cells (B6;129S4-Gcg em1(cre/ERT2)Khk /Mmjax) [36],  cells (B6.FVB(Cg)-Tg(Ucn3-cre)KF43Gsat/Mmucd) [37], or  cells (B6N.Cg-Sst tm2.1(cre)Zjh /J).…”

Section: Animalsmentioning

confidence: 99%

Free fatty-acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice

Croze¹,

Flisher

Guillaume³

et al. 2020

Preprint

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Objective: Maintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free-fatty acid receptor 4 (FFAR4/Gpr120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of Gpr120 remains unclear. As Gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that Gpr120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release. Methods: Glucose tolerance tests were performed in mice after administration of the selective Gpr120 agonist Cpd A. Gpr120 mRNA levels were assessed in pancreatic section by RNA in situ hybridization. Insulin, glucagon and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and pharmacological (Compound A and AZ-13581837) Gpr120 agonists. The effect of Compound A on hormone secretion was tested in islets isolated from mice with global or somatostatin cell-specific knockout (KO) of Gpr120. Calcium and cAMP dynamics in response to pharmacological Gpr120 agonists were measured in islets isolated from α, β, and δ cell-specific GCaMP6 and CAMPER reporter mice, respectively. Results: Acute exposure to Compound A increased glucose tolerance and circulating insulin and glucagon levels in vivo. Both pharmacological and endogenous Gpr120 agonists dose-dependently potentiated glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion and concomitantly reduced somatostatin secretion in isolated islets. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of Gpr120, and was partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin. Gpr120 agonists reduced forskolin-stimulated cAMP levels in δ cells, but did not evoke calcium signaling in islet cells. Conclusions: This study supports a key contribution of inhibitory Gpr120-Gαi/o signaling in δ cells in both insulin and glucagon secretion in part via mitigating somatostatin release.

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Interrogating the Spatiotemporal Landscape of Neuromodulatory GPCR Signaling by Real-Time Imaging of cAMP in Intact Neurons and Circuits

Cited by 32 publications

References 0 publications

Indirect Medium Spiny Neurons in the Dorsomedial Striatum Regulate Ethanol-Containing Conditioned Reward Seeking

Indirect Medium Spiny Neurons in the Dorsomedial Striatum Regulate Ethanol-Containing Conditioned Reward Seeking

Strategies for DevelopingκOpioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects

Free fatty-acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice

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