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  • Retinal GAL receptor distribution suggests an intrinsic neur


    Retinal GAL receptor distribution suggests an intrinsic neuronal control since retina lacks an autonomic innervation, and a signal modulation seems most likely here, acting via GALR1 while GALR2 and GALR3 seem to play a rather minor role in this signal transduction. While sources acting on these retinal GAL receptors in humans are unknown, species differences might exist since retinal GAL was not detected in rats (Hokfelt et al., 1992). Of interest is the detection of GALR2 in retinal vessels, that differs from the endothelial ciliary GALR3 and we interpret this as a consequence in different functional needs regarding tissue homeostasis. Choroidal GAL receptors were identified on intrinsic choroidal neurons. In humans as well as in some bird species these Aminoallyl-dUTP were reported being immunoreactive for several neuropeptides including GAL (May et al., 2004, Stubinger et al., 2010), and the various GAL receptors therefore most likely interact in the intrinsic neuronal network of the choroid, representing modulators of the autonomic nervous system. In line with these observations is the detected GALR1-3 perivascular immunoreactivity. If this immunoreactivity really matches with GAL-positive nerve fibers deriving from intrinsic or extrinsic sources or indeed mirrors the vascular target is not clear since this is beyond the resolution of the confocal microscope. The situation is different in the choriocapillaris since here an autonomic innervation is absent (Lutjen-Drecoll, 2006, Neuhuber and Schrodl, 2011) and therefore the observed GALR3-immunoreactivity most likely reflects the true receptor presence at the target site. A similar feature of the choriocapillaris, absence of innervation with receptor presence, is already known from the sympathetic nervous system: radioligand binding assays clearly demonstrated the presence of α2-adrenoreceptors in human RPE-choriocapillaris tissue (Bylund and Chacko, 1999) while adrenergic nerve fibers were lacking (Nuzzi et al., 1995). Striking is the receptor similarity between RPE and choriocapillaris, being mainly immunoreactive for GALR3, that might indicate the functional unit of these two tissues for the retinal supply and could have implications in retinal degenerative diseases (Kolomeyer and Zarbin, 2014).
    Acknowledgments Adele Rabensteiner Foundation, Austrian Academy of Sciences, Lotte Schwarz Endowment for Experimental Ophthalmology and Glaucoma Research, Research Fund of the Paracelsus Medical University (E-11713/068-SRO, FS; E-13/17/088-KAS, AK), The Fuchs Foundation and Austrian Research Promotion Agency (FFG: Project number: 822782/THERAPEP, BK).
    Data The dataset of this article provides information on GALR3 mutants that stabilize the receptor in either an agonist-bound or antagonist-bound form. Table 1 shows how 23 of the 210 point mutants expressed on VLPs increase [125I]-galanin binding and thermal stability compared to WT. In addition, a direct correlation of the Bmax values with recombinant expression yields of the mutants in Sf9 cultures was shown (Table 1 and Fig. 1). Combinations of these mutants were made to find the best thermostabilizing GALR3 agonist-bound (Table 2) and GALR3 antagonist-bound (Table 3) variants.
    Experimental design, materials and methods
    Introduction Galanin is a neuropeptide distributed in brain regions related to emotion, such as hippocampus, bed nucleus of the stria terminalis (BNST), dorsal raphe nucleus (DRN), and locus coeruleus of humans and other mammals [1]. The co-localization of galanin with serotonin in the DRN and with noradrenaline in the locus coeruleus also suggests an important function of this neuropeptide in the neurobiology of mood disorders [2,3]. Galanin can activate GAL1, GAL2 and GAL3 metabotropic receptors, which are widely distributed in the rat brain [4,5]. GAL1 and GAL3 usually mediate inhibitory actions by activating a Gi protein [4], whereas GAL2 can activate a Gq protein, inducing an intracellular Ca2+ concentration increase [4].