[PMID]: | 28592413 |
[Au] Autor: | Hardwick JC; Clason TA; Tompkins JD; Girard BM; Baran CN; Merriam LA; May V; Parsons RL |
[Ad] Endereço: | Department of Biology, Ithaca College, Ithaca, New York. |
[Ti] Título: | Recruitment of endosomal signaling mediates the forskolin modulation of guinea pig cardiac neuron excitability. |
[So] Source: | Am J Physiol Cell Physiol;313(2):C219-C227, 2017 Aug 01. |
[Is] ISSN: | 1522-1563 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | Forskolin, a selective activator of adenylyl cyclase (AC), commonly is used to establish actions of G protein-coupled receptors (GPCRs) that are initiated primarily through activation of AC/cAMP signaling pathways. In the present study, forskolin was used to evaluate the potential role of AC/cAMP, which is a major signaling mechanism for the pituitary adenylate cyclase-activating polypeptide (PACAP)-selective PAC1 receptor, in the regulation of guinea pig cardiac neuronal excitability. Forskolin (5-10 µM) increases excitability in ~60% of the cardiac neurons. The forskolin-mediated increase in excitability was considered related to cAMP regulation of a cyclic nucleotide gated channel or via protein kinase A (PKA)/ERK signaling, mechanisms that have been linked to PAC1 receptor activation. However, unlike PACAP mechanisms, forskolin enhancement of excitability was not significantly reduced by treatment with cesium to block currents through hyperpolarization-activated nonselective cation channels ( ) or by treatment with PD98059 to block MEK/ERK signaling. In contrast, treatment with the clathrin inhibitor Pitstop2 or the dynamin inhibitor dynasore eliminated the forskolin-induced increase in excitability; treatments with the inactive Pitstop analog or PP2 treatment to inhibit Src-mediated endocytosis mechanisms were ineffective. The PKA inhibitor KT5702 significantly suppressed the forskolin-induced change in excitability; further, KT5702 and Pitstop2 reduced the forskolin-stimulated MEK/ERK activation in cardiac neurons. Collectively, the present results suggest that forskolin activation of AC/cAMP/PKA signaling leads to the recruitment of clathrin/dynamin-dependent endosomal transduction cascades, including MEK/ERK signaling, and that endosomal signaling is the critical mechanism underlying the forskolin-induced increase in cardiac neuron excitability. |
[Mh] Termos MeSH primário: |
Adenilil Ciclases/metabolismo Colforsina/administração & dosagem Coração/efeitos dos fármacos Miocárdio/metabolismo Neurônios/efeitos dos fármacos
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[Mh] Termos MeSH secundário: |
Animais Carbazóis/administração & dosagem Clatrina/efeitos dos fármacos AMP Cíclico/metabolismo Proteínas Quinases Dependentes de AMP Cíclico/metabolismo Endossomos/efeitos dos fármacos Endossomos/metabolismo Flavonoides/administração & dosagem Cobaias Seres Humanos Sistema de Sinalização das MAP Quinases/efeitos dos fármacos Miocárdio/patologia Neurônios/metabolismo Neurônios/patologia Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo Pirróis/administração & dosagem Receptores Acoplados a Proteínas-G/metabolismo Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one); 0 (Carbazoles); 0 (Clathrin); 0 (Flavonoids); 0 (Pituitary Adenylate Cyclase-Activating Polypeptide); 0 (Pyrroles); 0 (Receptors, G-Protein-Coupled); 0 (Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I); 1F7A44V6OU (Colforsin); 58HV29I28S (KT 5720); E0399OZS9N (Cyclic AMP); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 4.6.1.1 (Adenylyl Cyclases) |
[Em] Mês de entrada: | 1708 |
[Cu] Atualização por classe: | 170907 |
[Lr] Data última revisão:
| 170907 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170609 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1152/ajpcell.00094.2017 |
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