RESUMO
Cell volume regulation is a basic homeostatic mechanism transcendental for the normal physiology and function of cells. It is mediated principally by the activation of osmolyte transport pathways that result in net changes in solute concentration that counteract cell volume challenges in its constancy. This process has been described to be regulated by a complex assortment of intracellular signal transduction cascades. Recently, several studies have demonstrated that alterations in cell volume induce the release of a wide variety of transmitters including hormones, ATP and neurotransmitters, which have been proposed to act as extracellular signals that regulate the activation of cell volume regulatory mechanisms. In addition, changes in cell volume have also been reported to activate plasma membrane receptors (including tyrosine kinase receptors, G-protein coupled receptors and integrins) that have been demonstrated to participate in the regulatory process of cell volume. In this review, we summarize recent studies about the role of changes in cell volume in the regulation of transmitter release as well as in the activation of plasma membrane receptors and their further implications in the regulation of the signaling machinery that regulates the activation of osmolyte flux pathways. We propose that the autocrine regulation of Ca2+-dependent and tyrosine phosphorylation-dependent signaling pathways by the activation of plasma membrane receptors and swelling-induced transmitter release is necessary for the activation/regulation of osmolyte efflux pathways and cell volume recovery. Furthermore, we emphasize the importance of studying these extrinsic signals because of their significance in the understanding of the physiology of cell volume regulation and its role in cell biology in vivo, where the constraint of the extracellular space might enhance the autocrine or even paracrine signaling induced by these released transmitters.
Assuntos
Comunicação Autócrina/fisiologia , Membrana Celular/metabolismo , Tamanho Celular , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/fisiologia , Animais , Homeostase , Humanos , Concentração Osmolar , Osmose , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
The chicken retina was exposed to 20% hyposmotic or ischaemia-like (54 mM KCl and 1 mM ouabain) conditions and changes in cell volume, amino acid release and activation of protein tyrosine kinases measured. To investigate possible connection between these cellular events, the effect of tyrosine kinase blockers on (3)H-taurine, (3)H-GABA and (3)H- D-aspartate (as a tracer for glutamate) efflux was examined. Both hyposmotic and ischaemic conditions increased phosphorylation of the tyrosine kinase p125 focal adhesion kinase (p125(FAK)) and the mitogen-activated protein kinase-p38 (MAPK-p38), but not of the extracellular-signal-related kinases-1/2 (ERK1/ERK2), and markedly activated the tyrosine kinase target enzyme phosphatidylinositide 3-kinase (PI3K). Hyposmolarity and ischaemia both led to rapid retinal swelling followed by active volume recovery of 84% (hyposmolarity) and 40% (ischaemia), together with rapid release of taurine, GABA and D-aspartate. Taurine and GABA efflux under both conditions was reduced markedly by tyrosine kinase and PI3K blockers (50 microM tyrphostin A23, 50 microM genistein, 100 nM wortmannin, 25 microM LY294002) and was decreased by 85% when ischaemia-induced swelling was prevented. About 65% of D-aspartate efflux occurred irrespective of swelling in ischaemia and was either less sensitive (hyposmotic) or largely resistant (ischaemia) to the blockers. These results suggest that in ischaemia, GABA and taurine react primarily to swelling with a typical osmolyte response, while glutamate differs in its release mechanisms under both hyposmotic and ischaemic conditions. These findings suggest new strategies for evaluating the contribution of swelling to excitotoxicity in ischaemia.