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Muscarinic acetylcholine receptors are prototypical G protein-coupled receptors (GPCRs), members of a large family of 7 transmembrane receptors mediating a wide variety of extracellular signals. We show here, in cultured cells and in a murine model, that the carboxyl terminal fragment of the muscarinic M2 receptor, comprising the transmembrane regions 6 and 7 (M2tail), is expressed by virtue of an internal ribosome entry site localized in the third intracellular loop. Single-cell imaging and import in isolated yeast mitochondria reveals that M2tail, whose expression is up-regulated in cells undergoing integrated stress response, does not follow the normal route to the plasma membrane, but is almost exclusively sorted to the mitochondria inner membrane: here, it controls oxygen consumption, cell proliferation, and the formation of reactive oxygen species (ROS) by reducing oxidative phosphorylation. Crispr/Cas9 editing of the key methionine where cap-independent translation begins in human-induced pluripotent stem cells (hiPSCs), reveals the physiological role of this process in influencing cell proliferation and oxygen consumption at the endogenous level. The expression of the C-terminal domain of a GPCR, capable of regulating mitochondrial function, constitutes a hitherto unknown mechanism notably unrelated to its canonical signaling function as a GPCR at the plasma membrane. This work thus highlights a potential novel mechanism that cells may use for controlling their metabolism under variable environmental conditions, notably as a negative regulator of cell respiration. The muscarinic M2 receptor is a prototypical G-protein-coupled receptor that mediates a wide range of extracellular signals. These authors show that the C-terminal fragment of M2 localizes to the mitochondrial inner membrane and is upregulated upon stress exposure, reducing cellular respiration and ROS to protect cells against variable environmental conditions. [ABSTRACT FROM AUTHOR]

"Ecstasy" [3,4-methylenedioxymetamphetamine (MDMA)] is of considerable interest in light of its prosocial properties and risks associated with widespread recreational use. Recently, it was found to bind trace amine-1 receptors (TA1Rs), which modulate dopaminergic transmission. Accordingly, using mice genetically deprived of TA1R (TA1-KO), we explored their significance to the actions of MDMA, which robustly activated human adenylyl cyclase-coupled TA1R transfected into HeLa cells. In wild-type (WT) mice, MDMA elicited a time-, dose-, and ambient temperature-dependent hypothermia and hyperthermia, whereas TA1-KO mice displayed hyperthermia only. MDMA-induced increases in dialysate levels of dopamine (DA) in dorsal striatum were amplified in TA1-KO mice, despite identical levels of MDMA itself. A similar facilitation of the influence of MDMA upon dopaminergic transmission was acquired in frontal cortex and nucleus accumbens, and induction of locomotion by MDMA was haloperidol-reversibly potentiated in TA1-KO versus WT mice. Conversely, genetic deletion of TA1R did not affect increases in DA levels evoked by para-chloroamphetamine (PCA), which was inactive at hTA1 sites. TheTA1Ragonist o-phenyl-3-iodotyramine (o-PIT) blunted the DA-releasing actions ofPCAboth in vivo (dialysis) and in vitro (synaptosomes) in WT but not TA1-KO animals. MDMA-elicited increases in dialysis levels of serotonin (5-HT) were likewise greater in TA1-KO versus WT mice, and 5-HT-releasing actions of PCA were blunted in vivo and in vitro by o-PIT in WT mice only. In conclusion, TA1Rs exert an inhibitory influence on both dopaminergic and serotonergic transmission, and MDMA auto-inhibits its neurochemical and functional actions by recruitment of TA1R. These observations have important implications for the effects of MDMA in humans. [ABSTRACT FROM AUTHOR]

Abstract: Though there is evidence that sustained exposure of dopamine (DA) receptors to agonists can elicit a supersensitivity of adenylyl cyclase (AC), little is known about the pharmacological characteristics of this phenomenon, and possible interrelationships amongst DA receptor subtypes have not been examined. In cells co-transfected with D1 plus D2, or D1 plus D3, receptors, which are known to physically and functionally interact, long-term exposure to quinpirole, pramipexole and ropinirole (which possess negligible affinities for D1 sites) elicited supersensitivity of D1 receptor-activated AC. By contrast, D2/D3 receptor agonists that also act as D1 receptor agonists, bromocriptine, lisuride, cabergoline, apomorphine and DA itself, did not elicit supersensitivity. Interestingly, AC supersensitivity was also observed in the nucleus accumbens of mice pretreated with twice-daily pramipexole and quinpirole, whereas no change was seen either with lisuride or with the DA precursor, l-DOPA. Thus, AC supersensitivity is elicited by the sustained exposure of cloned human and native mouse populations of dopaminergic receptors, to D2/D3 but not D1/D2/D3 agonists. These observations may be related to the exacerbation of gambling in Parkinson’s disease that is provoked by antiparkinson agents acting as selective D2/D3 receptor agonists, notably pramipexole. [ABSTRACT FROM AUTHOR]

Abstract: G-protein-coupled receptors (GPCRs) exist both as monomers and also as dimers or higher-order oligomers, representing assemblies either with their peers or with other classes of GPCR (“heterodimers”). The pharmacological profiles of heterodimers often differ from the corresponding monomers or homodimers. Heterodimerization of dopamine receptors has been shown for both the D1/D5 and D2/D3/D4 receptor families, which couple positively and negatively, respectively, to adenylyl cyclase. Notably, heterodimers are formed by: D1 and adenosine A1 receptors; D2 or D3 and adenosine A2 receptors; and D2 and somatostatin SST5 receptors. Further, D1,D2 and D3 receptors physically assemble into functional D1/D2,D1/D3 and D2/D3 heterodimers possessing binding and coupling profiles distinct from the respective monomers. This article reviews data on dopamine D3/D2 and D3/D1 heterodimers, including observations that some antiparkinsonian agents – such as the preferential high-efficacy D3 versus D2 receptor agonists, pramipexole and ropinirole –show amplified potency at D3/D2 heterodimers versus constituent monomers, and others in contrast, such as the D3/D2 receptor agonist pergolide, show no difference. This article also discusses allosteric modulation amongst heterodimeric dopamine receptors, whereby agonist actions at one member of a heterodimer influence functional coupling at the other protomer. Finally, it presents data showing that, in cells co-transfected with D3 and D1 receptors, long-term exposure to pramipexole and ropinirole (which possess negligible affinities for D1 sites) elicits supersensitivity of D1 receptor-activated adenylyl cyclase, and conversely, D3/D2 receptor agonists such as apomorphine and bromocriptine (which also act as D1 receptor agonists) do not. A hypothetical relationship between these observations and the exacerbation of gambling in Parkinson''s disease by antiparkinsonian agents is discussed. [Copyright &y& Elsevier]

(+)-4-Propyl-9-hydroxynaphthoxazine ((+)PHNO) is a high affinity, preferential dopamine D 3 versus D 2 agonist employed in view of its high specificity and excellent signal-to-noise ratio as a radiotracer for positron emission tomography (PET) imaging. Surprisingly, its profile at other classes of monoamine receptor remains undocumented. In addition to hD 3 and hD 2L receptors, (+)PHNO revealed high affinity at hD 4.4 but not hD 1 or hD 5 receptors. It also revealed significant affinity for several other G protein-coupled monoaminergic receptors, in particular h5-HT 1A and h5-HT 7 . (+)PHNO behaved as a full agonist at hD 4.4 and h5-HT 1A receptors with potencies comparable to its actions at hD 3 and hD 2L receptors, and with less potency at 5-HT 7 receptors. In binding assays with membranes derived from cells co-expressing hD 3 and hD 2L receptors and labeled with [ 3 H]Nemonapride or [ 3 H]Spiperone, the proportion of high affinity binding sites recognized by (+)PHNO was higher than an equivalent mixture of membranes from cells expressing hD 3 or hD 2L receptors, suggesting that (+)PHNO promotes formation of hD 3 -hD 2L heterodimers. Further, in cells co-expressing hD 3 and hD 2L receptors, (+)PHNO showed higher efficacy for inhibiting forskolin stimulated adenylyl cyclase and inducing adenylyl cyclase super-sensitization than in cells transfected with only hD 2L receptors. In conclusion, (+)PHNO is a potent agonist at hD 4 . 4 , h5-HT 1A and h5-HT 7 as well as hD 3 and hD 2L receptors, and it potently activates dopamine hD 3 -hD 2L heterodimers. These interactions should be considered when interpreting PET studies with [ 11 C](+)PHNO and may be relevant to its functional and potential clinical properties in Parkinson's disease and other disorders., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Recent data indicates that prolonged bright light exposure of rats induces production of neuromelanin and reduction of tyrosine hydroxylase positive neurons in the substantia nigra. This effect was the result of direct light reaching the substantia nigra and not due to alteration of circadian rhythms. Here, we measured the spectrum of light reaching the substantia nigra in rats and analysed the pathway that light may take to reach this deep brain structure in humans. Wavelength range and light intensity, emitted from a fluorescent tube, were measured, using a stereotaxically implanted optical fibre in the rat mesencephalon. The hypothetical path of environmental light from the eye to the substantia nigra in humans was investigated by computed tomography and magnetic resonance imaging. Light with wavelengths greater than 600 nm reached the rat substantia nigra, with a peak at 709 nm. Eyes appear to be the gateway for light to the mesencephalon since covering the eyes with aluminum foil reduced light intensity by half. Using computed tomography and magnetic resonance imaging of a human head, we identified the eye and the superior orbital fissure as possible gateways for environmental light to reach the mesencephalon.