Receptor Regulation of Osmolyte Homeostasis in Neural Cells in Response toHyposmotic Stress.

Cell Volume;Hyponatremia;Muscarinic;Potassium;Glutamate;Taurine;Pharmacy and Pharmacology;Health Sciences;Pharmacology

Foster, Daniel J.Traynor, John R. ;

University of Michigan

关键词: Cell Volume;    Hyponatremia;    Muscarinic;    Potassium;    Glutamate;    Taurine;    Pharmacy and Pharmacology;    Health Sciences;    Pharmacology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/77797/fosterdj_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Cell swelling can have profound deleterious effects in the brain and is observed to occur during several pathological conditions.Upon swelling, cells regulate their volume through the extrusion of various osmolytes.Prior studies in both chronically hyponatremic rat brains and cultures of primary astrocytes suggest that individual osmolytes are differentially utilized during cell volume regulation.In these models organic osmolytes are depleted from cells, whereas inorganic osmolytes are comparatively retained.Although selective osmolyte depletion has been appreciated for a number of years, the mechanism whereby this occurs has remained unknown.Activation of certain G-protein-coupled receptors, including muscarinic cholinergic receptors (mAChRs), has been demonstrated to non-selectively stimulate the release of both organic and inorganic osmolytes.However, the ability of the same receptors to regulate osmolyte influx has not been examined.I discovered that hypotonicity and receptor activation stimulated both the efflux and influx of K+ (monitored with 86Rb+) in SH-SY5Y cells and cultures of primary rat astrocytes.Furthermore, in SH-SY5Y cells, these fluxes (mediated primarily by K+ channels for efflux, and the Na+/K+ATPase and NKCC transporters for influx) were found to be of a similar magnitude so as to permit the retention of intracellular K+ during physiologically-relevant reductions in osmolarity.In contrast, taurine uptake (mediated via the taurine transporter) was inhibited by hypotonicity and mAChR activation in SH-SY5Y cells and cultured astrocytes.This process, when combined with increased taurine efflux, would promote taurine depletion.I also demonstrated that activation of mAChRs on SH-SY5Y cells, under isotonic conditions, resulted in an increased glutamate uptake (monitored as 3H-D-aspartate) and redistribution of the excitatory amino acid transporter 3 (EAAT3) to the plasma membrane.However, hypotonicity inhibited mAChR-mediated glutamate uptake and disrupted EAAT3 trafficking.Such a process may permit glutamate to be conserved within cells during small reductions in osmolarity, whereas depletion would occur under more hyposmotic conditions.Together, these findings suggest that GPCR-mediated regulation of osmolyte influx represents a potential mechanism whereby the selective depletion or retention of osmolytes is mediated.