Decoding the Signaling of a GPCR Heteromeric Complex Reveals a Unifying Mechanism of Action of Antipsychotic Drugs

Fribourg, Miguel; Moreno, José L.; Holloway, Terrell; Provasi, Davide; Baki, Lia; Mahajan, Rohit; Park, Chang Gyu; Adney, Scott K.; Hatcher, Candice N.; Eltit, José M.; Ruta, Jeffrey; Albizu, Laura; Li, Zheng; Umali, Adrienne; Shim, Jihyun; Fabiato, A; MacKerell, Alexander D.; Březina, Vladimír; Sealfon, Stuart C.; Filizola, Marta; González-Maeso, Javier; Logothetis, Diomedes E.

doi:10.1016/j.cell.2011.09.055

Cited by 269 publications

(303 citation statements)

References 58 publications

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“…We suggest that NKR can couple to multiple classes of G proteins, thereby providing a level of signaling diversity dependent on local G protein association. A recent study demonstrated a functional coassembly between G q -coupled (serotonin 5HT 2A receptor 2AR) and G i -coupled (metabotropic glutamate receptor mGluR2) receptors in cortical neurons, which sets a dynamic G q -G i balance of the resulting heteromeric receptor (44). It is conceivable that NKR in DRG may coassemble with a G i receptor, producing hybrid G q -G i signaling.…”

Section: Discussionmentioning

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.

107

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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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Section: Discussionmentioning

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.

107

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“…56 This glutamate receptor has been shown to be expressed in close molecular proximity with the 5-HT 2A receptor in tissue culture and mouse frontal cortex. 57,58 Although activation of the 5-HT 2A receptor in cortical pyramidal neurons is necessary to induce head-twitch by psychedelics, 27,45,46 these data suggest that other receptors, including CB 1 and mGlu2, are also involved in the modulation of their behavioral effects.…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

Animal Models of Serotonergic Psychedelics

Hanks

González-Maeso

2012

ACS Chem. Neurosci.

Self Cite

124

112

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The serotonin 5-HT 2A receptor is the major target of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Serotonergic psychedelics induce profound effects on cognition, emotion, and sensory processing that often seem uniquely human. This raises questions about the validity of animal models of psychedelic drug action. Nonetheless, recent findings suggest behavioral abnormalities elicited by psychedelics in rodents that predict such effects in humans. Here we review the behavioral effects induced by psychedelic drugs in rodent models, discuss the translational potential of these findings, and define areas where further research is needed to better understand the molecular mechanisms and neuronal circuits underlying their neuropsychological effects.KEYWORDS: Psychedelic, hallucinogenic, schizophrenia, psychosis, serotonin 5-HT 2A receptor, G protein-coupled receptor (GPCR), lysergic acid diethylamide (LSD), mouse behavior models E lucidating the mechanisms by which psychedelics induce their unique neuropsychological effects has important implications for a better understanding of behavioral processes such as cognition, perception, emotion, and sense of self. 1−5 The term psychedelic was coined in 1957 by the British psychiatrist Humphry Osmond to describe the effects of psychoactive drugs such as psilocybin, mescaline, and lysergic acid diethylamide (LSD). 6 These drugs belong to a larger group of substances known as hallucinogens, which also includes dissociatives (e.g., ketamine and phencyclidine), and deliriants (e.g., scopolamine and atropine), as well as compounds such as salvinorin A. Psychedelics all behave as agonists or partial agonists at the serotonin 5-HT 2A receptor, whereas dissociatives and deliriants have been identified as noncompetitive NMDA receptor antagonists, and competitive muscarinic receptor antagonists, respectively. Salvinorin A is a potent κ-opioid receptor agonist. 7−12 Although all of these hallucinogenic drugs profoundly alter perception, according to the Hallucinogen Rating Scale (HRS) and the Five-Dimensional Altered States of Consciousness (5D-ASC) rating scale, there are also features that are unique to each of these groups. 13−15 Research using behavioral and cognitive tasks indicates that different groups of hallucinogens induce overlapping, yet distinct sets of changes in sensory processing. Recent findings regarding the molecular mechanism of action of psychedelic and other hallucinogenic drugs have been reviewed elsewhere. 7,8,11,16−24 In this review, we will discuss the effects of psychedelics in a range of animal behavioral assays, and their utility as preclinical models of the effects of these drugs in humans. ■ MODELING PSYCHOSIS IN ANIMALSModeling in rodents the neuropsychological effects induced by psychedelic drugs remains controversial. The above-mentioned psychometric rating scales HRS and 5D-ASC measure aspects of subjective experience such as "oceanic boundlessness", "dread of ego dissolution", and "spiritual expe...

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“…Notably, the balance between G i -and G q -dependent signaling has been recently suggested to be an important parameter determining the ligand action on GPCR heteromers (29). This has been shown for mGluR2/5-HT 2A heteromers, which are composed of the G q -coupled 5-HT 2A receptor and the G i -coupled mGluR2 receptor (5) and for which the balance between G iand G q -dependent signaling predicts the anti-or propsychotic activity of drugs targeting mGluR2 and 5-HT 2A receptors.…”

Section: Discussionmentioning

confidence: 99%

Convergence of Melatonin and Serotonin (5-HT) Signaling at MT2/5-HT2C Receptor Heteromers

Kamal

Gbahou

Guillaume

et al. 2015

Journal of Biological Chemistry

106

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Background: There is cross-talk between serotonin and melatonin hormones. Results: There is evidence for unidirectional transactivation and a heteromer-specific signaling profile for formation of functional melatonin MT 2 and serotonin 5-HT 2C receptor heteromers. Conclusion: A new potential target of the antidepressant agomelatine is identified. Significance: The importance of binding of multitarget drugs to GPCR heteromers in psychiatric disorders is demonstrated.

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Decoding the Signaling of a GPCR Heteromeric Complex Reveals a Unifying Mechanism of Action of Antipsychotic Drugs

Cited by 269 publications

References 58 publications

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

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

Animal Models of Serotonergic Psychedelics

Convergence of Melatonin and Serotonin (5-HT) Signaling at MT2/5-HT2C Receptor Heteromers

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