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Exogenous myristoylated-Gi2α subunits of GTP-binding proteins are mitogens following their internalization by astrocytes in culture

AutorSánchez-Blázquez, Pilar ; De Antonio, I.; Montero, C.; Garzón, Javier
Palabras claveG protein α subunit Astrocyte Proliferation Confocal microscopy
Fecha de publicación2003
CitaciónMolecular Brain Research 110: 15- 26 (2003)
ResumenHeterotrimeric GTP-binding proteins (G proteins) are involved in the coupling of a variety of cell surface receptors to different intracellular signalling pathways, some of which take part in the regulation of growth by affecting cell proliferation and/or differentiation. In cultured astrocytes, many receptors of neuropeptides and hormones are coupled to the heterotrimeric Gi proteins which regulate the mitogen-activated protein kinase (MAPK/ERK) cascade through both the Gα and Gβγ subunits. We have previously reported that functionally active recombinant myr-Gi2α subunits added to such cultures are internalised and distributed within the plasma membrane and cytosol as well as in the nuclei of dividing astrocytes. Here we show that astrocytes proliferate dose-dependently in response to exogenous myr-Gi2α subunits. Concentrations of 100 pM-30 nM myr-Gi2α caused more than 2.5-fold increase of [3H]thymidine incorporation over basal levels. Other classes of myr-Gα subunits, such as Gi3α or Goα, induced a much lower proliferative effect. The addition of Gi1α subunits to the cultures produced no change, indicating the selectivity of this effect. Even though myr-Gi2α subunits are internalised by the cells regardless of their guanine nucleotide-bound state, much less [3H]thymidine incorporation was observed in the presence of GDPβS-myr-Gi2α or GTPγS-myr-Gi2α. Further, the fluorescent labelling was dissimilarly distributed, the signal being concentrated in the nucleus and perinuclear regions of the astrocytes. Selective disassembly of caveolae impaired both myr-Gi2α internalisation and DNA induction. Together, these data reveal a proliferative effect of myr-Gi2α subunits in astrocytes, and provide evidence for the incorporation of exogenous myr-Gi2α subunits into the mitogen cascade activated by neurotransmitters or growth factors. The fact that Gα proteins can enter cells is particularly interesting because options for delivering functional proteins into cells are limited. Thus, these proteins may have clinical applications for compensating deficits in the transduction mechanisms associated with several neurological diseases, or as a non-invasive membrane traversing carriers. © 2002 Elsevier Science B.V. All rights reserved.
Identificadoresdoi: 10.1016/S0169-328X(02)00554-5
issn: 0169-328X
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