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  • br Conclusions Beta cell specific expression in

    2022-07-01


    Conclusions Beta cell-specific expression in human islets of DGCR2, GBF1, GPR44 and SerpinB10 has not previously been described, although the proteins have partly been characterized in other contexts not related to beta buy ivermectin or diabetes. DGCR2, GPR44 and SerpinB10 were negative in all other cell types within pancreas and exposed epitopes at the cell surface, which make them suitable as potential targets for e.g. imaging. More studies are needed to confirm surface availability of the novel targets in vivo, as well as deeper understanding of the involvement of the targets in beta cell biology.
    Conflict of interest The following are the supplementary materials related to this article.
    Acknowledgments This work was supported by grants from the Knut and Alice Wallenberg Foundation, the Vinnova Foundation (2007-00069) and the Juvenile Diabetes Research Foundation (JDRF), grants 2009/371 and 2009/043. Human pancreatic islets were obtained from The Nordic Network for Clinical Islet Transplantation, supported by the Swedish national strategic research initiative EXODIAB (Excellence of Diabetes Research in Sweden) and the JDRF (award 31-2008-413).
    An Overview of GPCRs in the Nervous System The GPCR superfamily of seven transmembrane (7TM) receptors comprises the largest class of cell-membrane receptors [1]. GPCRs are activated by myriad stimuli including peptides, hormones, light, proteolytic processing of their N termini, small molecules, and more traditional protein ligands 2, 3. GPCRs have emerged as major pharmacological drug targets owing to their key roles in a variety of physiological functions in disease and health, and GPCR modulators represent at least one-third of all clinically marketed drugs [4]. GPCRs can be classified into five families using the phylogenetically based GRAFS system: glutamate, rhodopsin, adhesion, frizzled, and secretin [5]. Glutamate is a major excitatory neurotransmitter in the nervous system, and accordingly glutamate receptors have been studied in great detail with regard to their key roles in synaptic transmission, synapse formation, axon guidance, and the development of neuronal circuits 6, 7. The rhodopsin family has by far the greatest number of GPCRs, and family members are involved in photoreception and neurotransmission [5]. Frizzled GPCRs are activated by wingless/int (Wnt) proteins and control numerous cellular processes including neural crest development, patterning, and adult neurogenesis [8]. Secretin receptors are classic hormone receptors, some of which have neuroprotective functions in the CNS [9]. Finally, adhesion GPCRs represent the second largest GPCR family, with 33 human orthologs. Adhesion GPCRs play key developmental roles in many tissues, and recent work has highlighted their roles in nervous system development and disease 10, 11.
    GPCRs in Schwann Cell Development and Myelination
    GPCRs in Oligodendrocyte Development and Myelination > Concluding Remarks and Future Directions Myelin disruptions can lead to permanent neuron loss, significant pain, morbidity, and ultimately paralysis. Currently, no treatments exist to prevent demyelination or to enhance remyelination, partly because of our incomplete understanding of the genetic and molecular details of myelination. GPCRs are emerging as key regulators of myelinating glial cell development and myelin repair, but many discoveries remain to be made (see Outstanding Questions). To date, functions for only a handful of GPCRs in Schwann cells and oligodendrocytes have been described. In addition to obvious questions regarding ligand discovery for the known receptors, and uncovering other GPCRs present in myelinating glia, understanding how glial GPCRs interact – at the level of receptor multimerization at the cell surface as well as downstream signaling crosstalk and integration – is of fundamental importance. In the future, it will also be very interesting to explore ‘non-traditional’ modes of GPCR function in myelinating glia, including endosomal receptor signaling and biased agonism. Moreover, given the unparalleled pharmacologic potential of targeting GPCRs, understanding the mechanisms mediated by these receptors that underlie glial cell development and remyelination at the cellular and molecular levels has therapeutic potential to enhance myelin repair and functional recovery in patients.