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J. Biol. Chem., Vol. 278, Issue 49, 49308-49315, December 5, 2003

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A Bimodal Modulation of the cAMP Pathway Is Involved in the Control of Myogenic Differentiation in L6 Cells^*

Fabio Naro, Vania De Arcangelis, Claudio Sette¶, Caterina Ambrosio||, Hiba Komati**, Mario Molinaro, Sergio Adamo, and Georges Nemoz**

From the Dipartimento di Istologia ed Embriologia Medica, Università "La Sapienza," 00161 Rome, Italy, ^**INSERM U585, Physiopathologie des Lipides et Membranes, INSA de Lyon, 69621 Villeurbanne, France, the ^¶Dipartimento di Sanità Pubblica e Biologia Cellulare, Sezione di Anatomia, Università "Tor Vergata," 00173 Rome, Italy, and the ^||Dipartimento di Farmacologia, Istituto Superiore di Sanità, 00161 Rome, Italy

We have previously shown that myogenesis induction by Arg⁸-vasopressin (AVP) in L6 rat myoblasts involves a sustained stimulation of type 4 cAMP-phosphodiesterase. In this model, we observed that a transient cAMP generation occurs in the minutes following AVP addition. Evidence suggests that cAMP generation is due to the prostaglandins produced in response to AVP binding to V1a receptors and subsequent activation of phospholipase A2. The early cAMP increase was effective in activating cAMP-dependent protein kinase (PKA) and increasing phosphorylation of CREB transcription factor. Inhibition of PKA by compound H89 prior to AVP addition led to a significant reduction of expression of the differentiation marker creatine kinase, whereas H89 added 1-5 h after AVP had no significant effect. Furthermore, PKA inhibition 24 h after the beginning of AVP treatment potentiated differentiation. This shows that both an early activation and a later down-regulation of the cAMP pathway are required for AVP induction of myogenesis. Because phosphodiesterase PDE4D3 overexpressed in L6 cells lost its ability to potentiate AVP-induced differentiation when mutated and rendered insensitive to PKA phosphorylation and activation, we hypothesize that the early cAMP increase is required to trigger the down-regulation of cAMP pathway through stimulation of phosphodiesterase.

Received for publication, June 30, 2003 , and in revised form, September 22, 2003.

^* This work was supported by grants from the Ministero Istruzione Università e Ricerca (to S. A. and M. M.), from University of Rome-La Sapienza (to S. A. and F. N.), and from Centro di Eccellenza Biologia e Medicina Molecolare. The exchanges between the collaborating institutions were supported by a Consiglio Nazionale delle Ricerche-Institut National de la Santé et de la Recherche Médicale joint program grant (to G. N. and S. A.). 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: Dipartimento di Istologia ed Embriologia Medica, Università di Roma La Sapienza, 00161 Rome, Italy. Tel.: 39-06-4976-6587; Fax: 39-06-4462-854; E-mail: fabio.naro{at}uniroma1.it.

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