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  • Further important evidence for G protein signaling on early

    2024-05-15

    Further important evidence for G protein signaling on early endosomes has been subsequently obtained for the β2-adrenegic receptor using fluorescently-tagged conformation-sensitive nanobodies selectively recognizing the active receptor and Gs protein [43]. More recently, our group used a combination of sensors based fluorescence resonance energy transfer (FRET) and a nanobody recognizing the active Gs protein to localize the subcellular compartment where endogenous TSH receptors are signaling in primary thyroid (-)-p-Bromotetramisole Oxalate mg [44]. We found that the TSH receptor co-internalizes with TSH and traffics retrogradely to the trans-Golgi network, where it activates an endogenous pool of Gs protein. This leads to a delayed phase of local cAMP production and PKA activation at a critical position near the nucleus, which appears required for efficient CREB phosphorylation and gene transcription in response to TSH [44]. In contrast to previous observations with the PTH receptor, however, retromer was found to promote persistent TSH receptor signaling [44]. A requirement of receptor internalization for gene transcription has also been demonstrated for the β2 adrenergic receptor [45]. Moreover, signaling in the Golgi complex has also been demonstrated for the β1-adrenergic receptor [46]. However, in the case of the β1-adrenergic receptor, it has been suggested that adrenalin, which is hydrophilic, crosses cellular membranes via the organic cation transporter 3 (OCT3) and reaches a pool of β1-adrenergic receptors that reside in the Golgi complex [46]. In the meantime, signaling at intracellular membranes has been reported for several GPCRs, including the dopamine D1 receptor [47], vasopressin V2 receptor [48], glucagon-like peptide 1 (GLP1) receptor [49], pituitary adenylate cyclase activating polypeptide 1 (PACAP1) receptor [50] and glucose-dependent insulinotropic peptide (GIP) receptor [51]. A question left open by these studies was related to the apparent contrasting role of β-arrestins, which have a well-established role in signal desensitization and, at the same time, have been suggested to promote endosomal signaling. Intriguingly, recent structural studies indicate that β-arrestins can engage with two different domains of GPCRs, i.e. with either the C-tail or the seven-transmembrane core [52]. Moreover, a complex consisting of a receptor with the G protein bound to its seven-transmembrane core and β-arrestin 1 simultaneously bound to its C-tail has been directly observed by cry-electron microscopy [53]. All these studies suggest the existence of multiple intracellular locations for GPCR signaling (Fig. 1). Some receptors, like the PTH and the β2-adrenergic receptor, seem to signal prevalently from early endosomes. In contrast, the TSH and the β1-adrennergic receptor signal on membranes of the Golgi/trans-Golgi network. Furthermore, there is evidence for GPCR signaling at other intracellular compartments such as the nuclear envelope [54] and, more recently, mitochondria. Indeed, cannabinoid CB1 receptors have been shown to be located on brain mitochondrial membranes, where they have been suggested to play a role in the amnesic effects of cannabinoids [55]. Similarly, melatonin has been shown to be produced inside neuronal mitochondria, where it activates local MT1 receptors [56]. The resulting signaling prevents stress-mediated cytochrome c release and caspase activation, thus contributing to melatonin neuroprotective effects [56]. Although we are only beginning to understand the implications of such a high degree of spatial control and complexity in GPCR signaling, it is likely that these mechanisms play an important role in allowing to discriminate among the multitude of extracellular signals that converge on a single cell.
    Role of receptor internalization and trafficking in physiology and disease Consistent with their crucial role of in GPCR signaling, receptor internalization and trafficking are deeply implicated in human physiology and, most likely, also in disease. A first important aspect regards the correct subcellular localization of receptors. Indeed, genetic mutations affecting receptor trafficking and causing reduced cell surface localization of receptors are known to be implicated in various human diseases, such as TSH resistance, familial idiopathic hypogonadotropic hypogonadism, Leydig cell hypoplasia or familial glucocorticoid deficiency [57].