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Distinct Potentiation of L-Type Currents and Secretion by cAMP in Rat Chromaffin Cells

V. Carabelli ^*, A. Giancippoli ^*, P. Baldelli ^*, E. Carbone ^* and A. R. Artalejo 

^* Dipartimento di Neuroscienze, Unità di Ricerca, Instituto Nazionale Fisica della Materia, 10125 Turin, Italy; and Departamento de Toxicología y Farmacología, Universidad Complutense, 28040 Madrid, Spain

Correspondence: Address reprint requests to Dr. Valentina Carabelli, Department of Neuroscience, Corso Raffaello 30, 10125 Turin, Italy. Tel.: +39-011-6707702; Fax: +39-011-6707708; E-mail: valentina.carabelli{at}unito.it.

We have investigated the potentiating action of cAMP on L-currents of rat chromaffin cells and the corresponding increase of Ca²⁺-evoked secretory responses with the aim of separating the action of cAMP on Ca²⁺ entry through L-channels and the downstream effects of cAMP/protein kinase A (PKA) on exocytosis. In -toxin-treated rat chromaffin cells, exposure to the permeable cAMP analog 8-(4-chlorophenylthio)-adenosine 3',5'-monophosphate (pCPT-cAMP; 1 mM, 30 min) caused a moderate increase of Ca²⁺ charge carried through L-channels (19% in 10 mM Ca²⁺ at +10 mV) and a drastic potentiation of secretion (100%), measured as membrane capacitance increments (C). The apparent Ca²⁺ dependency of exocytosis increased with pCPT-cAMP and was accompanied by 83% enhancement of the readily releasable pool of vesicles with no significant change of the probability of release, as evaluated with paired-pulse stimulation protocols. pCPT-cAMP effects could be mimicked by stimulation of ß₁-adrenoreceptors and reversed by the PKA inhibitor H89, suggesting strict PKA dependence. For short pulses to +10 mV (100 ms), potentiation of exocytosis by pCPT-cAMP was proportional to the quantity of charge entering the cell and occurred independently of whether L, N, or P/Q channels were blocked, suggesting that cAMP acts as a constant amplification factor for secretion regardless of the channel type carrying Ca²⁺. Analysis of statistical variations among depolarization-induced capacitance increments indicates that pCPT-cAMP acts downstream of Ca²⁺ entry by almost doubling the mean size of unitary exocytic events, most likely as a consequence of an increased granule-to-granule rather than a granule-to-membrane fusion.

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