Synergistic Ca2+ Responses by Gαi- and Gαq-coupled G-protein-coupled Receptors Require a Single PLCβ Isoform That Is Sensitive to Both Gβγ and Gαq

Rebres, Robert A.; Roach, T. I. A.; Fraser, Iain D. C.; Philip, Finly; Moon, Christina; Lin, Keng Mean; Liu, Jamie; Santat, Leah A.; Cheadle, Lucas; Ross, Elliott M.; Simon, Melvin I.; Seaman, William E.

doi:10.1074/jbc.m110.198200

Cited by 55 publications

(49 citation statements)

References 51 publications

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“…8). In fact, the D 4 R did not support a calcium response in the presence of coexpressed D 1 R, indicating that nonspecific G i -G q cross-talk, at least as previously described (Okajima et al, 1989;Carroll et al, 1995;Toms and Roberts, 1999;Rebres et al, 2011). does not explain the D 1 -D 2 heteromer-mediated calcium response.…”

Section: Table 1 Skf93959 Competition Binding Experiments Against Varmentioning

confidence: 80%

“…Multiple cases of G i -G q cross-talk in other receptor systems and cell types have been documented (Okajima et al, 1989;Carroll et al, 1995;Toms and Roberts, 1999;Rebres et al, 2011), and G i -G q cross-talk in the D 1 -D 2 receptor system could account for the PTX sensitivity of the calcium signal. In this model, any G i -linked GPCR, not just the D 2 R, would be able to support a G q -mediated calcium response.…”

Section: Table 1 Skf93959 Competition Binding Experiments Against Varmentioning

confidence: 99%

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D₁-D₂Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

et al. 2013

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The D 1 dopamine receptor (D 1 R) has been proposed to form a hetero-oligomer with the D 2 dopamine receptor (D 2 R), which in turn results in a complex that couples to phospholipase Cmediated intracellular calcium release. We have sought to elucidate the pharmacology and mechanism of action of this putative signaling pathway. Dopamine dose-response curves assaying intracellular calcium mobilization in cells heterologously expressing the D 1 and D 2 subtypes, either alone or in combination, and using subtype selective ligands revealed that concurrent stimulation is required for coupling. Surprisingly, characterization of a putative D 1 -D 2 heteromer-selective ligand, 6-chloro-2,3,4,5-tetrahydro-3-methyl-1-(3-methylphenyl)-1H-3-benzazepine-7,8-diol (SKF83959), found no stimulation of calcium release, but it did find a broad range of cross-reactivity with other G protein-coupled receptors. In contrast, SKF83959 appeared to be an antagonist of calcium mobilization. Overexpression of G qa with the D 1 and D 2 dopamine receptors enhanced the dopamine-stimulated calcium response. However, this was also observed in cells expressing G qa with only the D 1 R. Inactivation of G i or G s with pertussis or cholera toxin, respectively, largely, but not entirely, reduced the calcium response in D 1 R and D 2 R cotransfected cells. Moreover, sequestration of G bg subunits through overexpression of G protein receptor kinase 2 mutants either completely or largely eliminated dopamine-stimulated calcium mobilization. Our data suggest that the mechanism of D 1 R/D 2 R-mediated calcium signaling involves more than receptor-mediated G q protein activation, may largely involve downstream signaling pathways, and may not be completely heteromer-specific. In addition, SKF83959 may not exhibit selective activation of D 1 -D 2 heteromers, and its significant cross-reactivity to other receptors warrants careful interpretation of its use in vivo.

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Section: Table 1 Skf93959 Competition Binding Experiments Against Varmentioning

confidence: 80%

Section: Table 1 Skf93959 Competition Binding Experiments Against Varmentioning

confidence: 99%

D₁-D₂Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

et al. 2013

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“…G␣ q and G␤␥ can simultaneously activate PLC-␤ isozymes, and this activation may be important for the integration of signals downstream of multiple, activated G protein-coupled receptors (51). For PLC-␤2 and especially PLC-␤3, this activation can be synergistic and requires low basal phospholipase activity (52).…”

Section: Discussionmentioning

confidence: 99%

Membrane-induced Allosteric Control of Phospholipase C-β Isozymes

Charpentier

Waldo

Barrett

et al. 2014

Journal of Biological Chemistry

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Background: Phospholipase C-␤ (PLC-␤) isozymes hydrolyze phosphatidylinositol 4,5-bisphosphate to propagate signals for several physiological responses. Results: Membranes are essential for the allosteric release of autoinhibition of PLC-␤ isozymes. Conclusion: Activators of PLC-␤ release autoinhibition by orientating the isozymes at the membrane. Significance: The model described provides a better understanding of PLC-␤ regulation and potential mechanisms to inhibit their activation.

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“…Interestingly, SP-mediated M-current augmentation in DRG neurons was blocked by the PLC inhibitor edelfosine (10 μM): Nine of nine edelfosine-treated neurons showed no augmentation (Fig S3 D). These experiments suggest that in DRG and TG neurons the effect of SP is mediated by G i/o protein and a PLC isoform that is not coupled to G q/11 exclusively but also can be activated by G i/o [e.g., PLC β2 or β3 (35)]. …”

Section: Sp Augments M Current In Sensory Neurons Via Oxidativementioning

confidence: 99%

Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons

Linley¹,

Ooi

Pettinger³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

108

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Substance P (SP) is a prominent neuromodulator, which is produced and released by peripheral damage-sensing (nociceptive) neurons; these neurons also express SP receptors. However, the mechanisms of peripheral SP signaling are poorly understood. We report a signaling pathway of SP in nociceptive neurons: Acting predominantly through NK1 receptors and G i/o proteins, SP stimulates increased release of reactive oxygen species from the mitochondrial electron transport chain. Reactive oxygen species, functioning as second messengers, induce oxidative modification and augment M-type potassium channels, thereby suppressing excitability. This signaling cascade requires activation of phospholipase C but is largely uncoupled from the inositol 1,4,5-trisphosphate sensitive Ca 2+ stores. In rats SP causes sensitization of TRPV1 and produces thermal hyperalgesia. However, the lack of coupling between SP signaling and inositol 1,4,5-trisphosphate sensitive Ca 2+ stores, together with the augmenting effect on M channels, renders the SP pathway ineffective to excite nociceptors acutely and produce spontaneous pain. Our study describes a mechanism for neurokinin signaling in sensory neurons and provides evidence that spontaneous pain and hyperalgesia can have distinct underlying mechanisms within a single nociceptive neuron.G protein coupled receptors | inflammatory pain | intracellular signaling | KCNQ | M current E xcitation of peripheral terminals of sensory neurons is a primary event in somatosensation, including pain. A large proportion of sensory neurons (mostly TRPV1 + damage-sensing or "nociceptive" neurons) produce neuropeptides such as substance P (SP), which are released in response to nociceptive stimulation both at spinal cord synapses and in the periphery (1). In the spinal cord SP acts as an excitatory neurotransmitter or cotransmitter (2, 3), whereas peripheral SP release is thought to underlie the inflammatory response known as "neurogenic inflammation" (4). Many peripheral nociceptors also express receptors for SP [neurokinin receptors (NKR) 1-3 (NK1-3)]; this expression may suggest paracrine or autocrine actions of this peptide. However, the nature of such actions is controversial, and the molecular events triggered by NKR in peripheral nociceptors are not well established. The NKR traditionally are classed as G q/11 -coupled G protein-coupled receptors (GPCR) that activate phospholipase C (PLC), with subsequent hydrolysis of membrane phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and release of inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG) (5, 6). Common downstream steps of G q/11 signaling include IP 3 -mediated release of Ca 2+ from intracellular stores and DAG-mediated activation of PKC. However, it was hitherto unknown whether NKR in peripheral sensory neurons couple fully to this signaling cascade, because a lack of coupling between NKR and Ca 2+ release in dorsal root ganglia (DRG) neurons has been noted (ref. 7 and 8, but cf. ref. 9). Nevertheless, it is accepted that peripherally act...

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Synergistic Ca2+ Responses by Gαi- and Gαq-coupled G-protein-coupled Receptors Require a Single PLCβ Isoform That Is Sensitive to Both Gβγ and Gαq

Cited by 55 publications

References 51 publications

D₁-D₂Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

D₁-D₂Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

Membrane-induced Allosteric Control of Phospholipase C-β Isozymes

Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons

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Synergistic Ca2+ Responses by Gαi- and Gαq-coupled G-protein-coupled Receptors Require a Single PLCβ Isoform That Is Sensitive to Both Gβγ and Gαq

Cited by 55 publications

References 51 publications

D1-D2Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

D1-D2Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

Membrane-induced Allosteric Control of Phospholipase C-β Isozymes

Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons

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D₁-D₂Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms

D₁-D₂Dopamine Receptor Synergy Promotes Calcium Signaling via Multiple Mechanisms