Group I Metabotropic Glutamate Receptors Mediate a Dual Role of Glutamate in T Cell Activation

Abstract

Metabotropic glutamate receptors (mGluR) are present in cells of the nervous system, where they are activated by one of the main neurotransmitters, glutamate. They are also expressed in cells outside the nervous system. We identified and characterized two receptors belonging to group I mGluR, mGlu1R and mGlu5R, in human cell lines of lymphoid origin and in resting and activated lymphocytes from human peripheral blood. Both are highly expressed in the human Jurkat T cell line, whereas mGlu5R is expressed only in the human B cell line SKW6.4. In blood lymphocytes, mGlu5R is expressed constitutively, whereas mGlu1R is expressed only upon activation via the T cell receptor-CD3 complex. Group I receptors in the central nervous system are coupled to phospholipase C, whereas in blood lymphocytes, activation of mGlu5R does not trigger this signaling pathway, but instead activates adenylate cyclase. On the other hand, mGlu5R does not mediate ERK1/2 activation, whereas mGlu1R, which is coupled neither to phospholipase C nor to calcium channels and whose activation does not increase cAMP, activates the mitogen-activated protein kinase cascade. The differential expression of mGluR in resting and activated lymphocytes and the different signaling pathways that are triggered when mGlu1Rs or mGlu5Rs are activated point to a key role of glutamate in the regulation of T cell physiological function. The study of the signaling pathways (cAMP production and ERK1/2 phosphorylation) and the proliferative response obtained in the presence of glutamate analogs suggests that mGlu1R and mGlu5R have distinct functions. mGlu5R mediates the reported inhibition of cell proliferation evoked by glutamate, which is reverted by the activation of inducible mGlu1R. This is a novel non-inhibitory action mechanism for glutamate in lymphocyte activation. mGlu1R and mGlu5R thus mediate opposite glutamate effects in human lymphocytes.There is increasing evidence that the activity of T cells in the central nervous system is regulated by neurotransmitters such as dopamine, gonadotropin-releasing hormones I and II, somatostatin, substance P, calcitonin-gene-related peptide, neuropeptide Y, and glutamate (1). The latter is the main excitatory neurotransmitter in the mammalian brain involved in learning and memory, as well as in neurotoxicity, and plays a critical role in the development and progression of diverse neurological disorders. T cells can also encounter glutamate outside the brain, in "glutamate-rich" peripheral organs such as liver, kidney, lung, muscle, and blood. It is unknown whether glutamate can be released by antigen-presenting cells, thus regulating T cell activation in the immunological synapse (2).This amino acid acts at multiple receptor types, divided into two main groups: ionotropic glutamate receptors, which form ion channels and mediate fast excitatory glutamate responses, and metabotropic glutamate receptors (mGluR), 1 which are hepta-spanning membrane-receptors and belong to the superfamily of G protein-coupled receptors (3). So f...

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