Identification of intracellular signaling cascades mediating the PACAP-induced increase in guinea pig cardiac neuron excitability.
J Mol Neurosci
; 36(1-3): 292-8, 2008 Nov.
Article
em En
| MEDLINE
| ID: mdl-18509761
ABSTRACT
The pituitary adenylate cyclase-activating polypeptide (PACAP) increases excitability of guinea pig cardiac neurons, an effect mediated through activation of PAC1 receptors. The signaling cascades that couple activation of the PAC1 receptor to alterations in membrane ionic conductances responsible for the PACAP effect are unknown. Intracellular recordings were made from neurons in kinase inhibitor-treated cardiac ganglia preparations to determine which of the intracellular cascades activated by PAC1 receptor stimulation mediate the PACAP effect. In control cells, long depolarizing-current steps elicited one to three action potentials. In contrast, during the application of 10 nM PACAP, depolarizing-current pulses elicited multiple action potential firing (greater than or equal to five action potentials) in 79% of the neurons. Pretreatment with an adenylyl cyclase inhibitor, SQ 22536 (100 microM), suppressed the PACAP-induced increase in excitability, whereas the presence of U-73122 (10 microM), a potent phospholipase C (PLC) inhibitor, had no effect. Thus, the activation of adenylyl cyclase, but not PLC, was a critical step mediating the PACAP effect. Pretreatment with H-89 (1 microM), a protein kinase A inhibitor, and PD 98059 (50 microM), a MEK kinase inhibitor, also significantly blunted the PACAP-induced increase in excitability. Furthermore, treatment with forskolin (5 microM), an activator of adenylyl cyclase, or exposure to the cell-permeable cyclic adenosine monophosphate (cAMP) analogue, 8-bromo-cAMP (1 mM), partially recapitulated the effect of PACAP on excitability. We conclude that the activation of signaling cascades downstream of cAMP mediate the PACAP-induced increase in cardiac neuron excitability.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Fibras Parassimpáticas Pós-Ganglionares
/
Polipeptídeo Hipofisário Ativador de Adenilato Ciclase
/
Miocárdio
/
Neurônios
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article