18, 68 -69). We identified and localized in rat skeletal muscle myoblasts a functional serotonin 5-HT 2A receptor. This receptor was detected on the plasma membrane, in myoblasts, and at the level of T-tubules in contracting myotubes. Binding of serotonin to its receptor increases the expression of genes involved in myogenic differentiation. Unexpectedly, the 5-HT 2A receptor is able to activate another signaling pathway; it triggers a rapid and transient tyrosine phosphorylation of Jak2 kinase in response to serotonin. Jak2 auto-phosphorylation is followed by the tyrosine phosphorylation of STAT3 (signal transducers and activators of transcription) and its translocation into the nucleus. We also find that the 5-HT 2A receptor and STAT3 co-precipitate with Jak2, indicating that they are physically associated. We conclude that the serotonin 5-HT 2A receptor identified in skeletal muscle myoblasts is able to activate the intracellular phosphorylation pathway used by cytokines. The presence of serotonin receptors in T-tubules suggests a role for serotonin in excitation-contraction coupling and (or) an effect in skeletal muscle fiber repairing. Serotonin (5-hydroxytryptamine, 5-HT)1 is a neurotransmitter that mediates diverse central and peripheral physiological responses by interacting with multiple serotonin receptor subtypes (1). The physiological effects of serotonin are mediated by at least four families of 5-HT receptors that have been distinguished pharmacologically, depending on the second messenger they are coupled to. The first family, including 5-HT 1 and 5-HT 5 receptor subtypes, interacts negatively with adenylate cyclase, whereas the second family (5-HT 2 ) is coupled to the activation of phospholipase C-/protein kinase C. The 5-HT 3 receptor is a ligand-gated ion channel, and the family including 5-HT 4 , 5-HT 6 , and 5-HT 7 receptor subtypes activates adenylate cyclase (2). The receptors of the 5-HT 2 subfamily are implicated in many central physiological functions of serotonin, such as neuronal sensitization to tactile stimuli and mediation of hallucinogenic effects of lysergic acid diethylamide, as well as in peripheral cardiovascular effects, e.g. contraction of blood vessels and shape change in platelets. The 5-HT 2A (formerly 5-HT 2 ) receptor shares an overall 49% sequence identity with the 5-HT 2C (formerly 5-HT 1C ) receptor, but they present different patterns of expression in the brain (3). Transfection of both 5-HT 2C and 5-HT 2A receptors in NIH3T3 fibroblasts results in cellular transformation and focus formation (3). The mouse 5-HT 2B receptor, mainly expressed in the cardiovascular system, gut, and developing brain (4), shares the highest degree of homology with the other 5-HT 2B receptors cloned from the rat fundus or from human libraries (5). The 5-HT 2B receptor has been classified as a ligand-dependent proto-oncogene, since its expression is necessary and sufficient to induce tumor formation in nude mice (6).Serotonin 5-HT 2A receptors have been mainly localized in frontal cortex ...
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