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J. Biol. Chem., Vol. 279, Issue 30, 31081-31088, July 23, 2004

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ATP Potentiates Agrin-induced AChR Aggregation in Cultured Myotubes

ACTIVATION OF RHOA IN P2Y₁ NUCLEOTIDE RECEPTOR SIGNALING AT VERTEBRATE NEUROMUSCULAR JUNCTIONS^*

Karen K. Y. Ling, Nina L. Siow, Roy C. Y. Choi, Annie K. L. Ting, Ling W. Kong, and Karl W. K. Tsim¶

From the Department of Biology and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Hong Kong, China

At vertebrate neuromuscular junctions, ATP is known to stabilize acetylcholine in the synaptic vesicles and to be co-released with it. We have shown previously that a nucleotide receptor, P2Y₁ receptor, is localized at the nmjs, and we propose that this mediates a trophic role for synaptic ATP there. In cultured myotubes, the activation of P2Y₁ receptors modulated agrin-induced acetylcholine receptor (AChR) aggregation in a potentiation manner. This potentiation effect in agrin-induced AChR aggregation was reduced by antagonizing the P2Y₁ receptors. The guanosine triphosphatase RhoA was shown to be responsible for this P2Y₁-potentiated effect. The localization of RhoA in rat and chicken skeletal muscles was restricted at the neuromuscular junctions. Application of P2Y₁ agonists in cultured myotubes induced RhoA activation, which showed an additive effect with agrin-induced RhoA activation. Over-expression of dominant-negative mutant of RhoA in cultured myotubes diminished the agrin-induced AChR aggregation, as well as the potentiation effect of P2Y₁-specific agonist. Application of UTP in the cultures also triggered similar responses as did 2-methylthioadenosine 5'-diphosphate, suggesting the involvement of other subtypes of P2Y receptors. These results demonstrate that RhoA could serve as a downstream mediator of signaling mediated by P2Y₁ receptor and agrin, which therefore synergizes the effects of the two neuron-derived trophic factors in modulating the formation and/or maintenance of post-synaptic apparatus at the neuromuscular junctions.

Received for publication, March 25, 2004 , and in revised form, April 28, 2004.

^* This work was supported by Grants HKUST 6098/02 M and 6283/03 M from the Research Grants Council of Hong Kong (to K. W. K. T.). 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.

Recipient of a Croucher Foundation Scholarship.

Supported by the post-doctoral matching fund from Hong Kong University of Science and Technology.

^¶ To whom correspondence should be addressed: Dept. of Biology, Hong Kong University of Science and Technology, Clear Water Bay Road, Kowloon, Hong Kong SAR, China. Tel.: 852-2358-7332; Fax: 852-2358-1559; E-mail: botsim{at}ust.hk.

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