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J. Biol. Chem., Vol. 278, Issue 36, 34150-34157, September 5, 2003

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Modulation of 5-HT₃ Receptor-mediated Response and Trafficking by Activation of Protein Kinase C^*

Hui Sun, Xian-Qun Hu, Edgar M. Moradel, Forrest F. Weight and Li Zhang 

From the Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-8115

Modulation of neurotransmitter-gated membrane ion channels by protein kinase C (PKC) has been the subject of a number of studies. However, less is known about PKC modulation of the serotonin type 3 (5-HT₃) receptor, a ligand-gated membrane ion channel that can mediate fast synaptic transmission in the central and peripheral nervous system. Here, we show that PKC potentiated 5-HT₃ receptor-mediated current in Xenopus oocytes expressing 5-HT_3A receptors and mouse N1E-115 neuroblastoma cells. In addition, using a specific antibody directed to the extracellular N-terminal domain of the 5-HT_3A receptor, treatment with the PKC activator, 4-phorbol 12-myristate 13-acetate (PMA), significantly increased surface immunofluorescence. PKC also increased the amount of 5-HT_3A receptor protein in the cell membrane without affecting the amount receptor protein in the total cell extract. The magnitude of PMA potentiation of 5-HT_3A receptor-mediated responses is correlated with the magnitude of PMA enhancement of the receptor abundance in the cell surface membrane. PMA potentiation is unlikely to occur via direct phosphorylation of the 5-HT_3A receptor protein since the potentiation was not affected by point mutation of each of the putative sites for PKC phosphorylation. However, preapplication of phalloidin, which stabilizes the actin polymerization, significantly inhibited PMA potentiation of 5-HT-activated responses in both N1E-115 cells and oocytes expressing 5-HT_3A receptors. On the other hand, latrunculin-A, which destabilizes actin cytoskeleton, enhanced the PMA potentiation of 5-HT_3A receptors. The observations suggest that PKC can modulate 5-HT_3A receptor function and trafficking through an F-actin-dependent mechanism.

Received for publication, April 7, 2003 , and in revised form, May 30, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, Park Bldg., Rm. 150, Bethesda, MD 20892-8115. Tel.: 301-443-1236; Fax: 301-480-6882; E-mail: lzhang{at}niaaa.nih.gov.

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