Prostaglandin E2-induced modification of tetrodotoxin-resistant Na+ currents involves activation of both EP2 and EP4 receptors in neonatal rat nodose ganglion neurones

摘要: The aim of the present study was to investigate which EP receptor subtypes (EP1–EP4) act predominantly on modification tetrodotoxin-resistant Na+ current (INaR) in acutely isolated neonatal rat nodose ganglion (NG) neurones. Of four agonists ranging from 0.01 10 μM, EP2 agonist (ONO-AE1-259, 0.1–10 μM) and EP4 (ONO-AE1-329, 1 μM) significantly increased peak INaR. responses were associated with a hyperpolarizing shift activation curve. Neither EP1 ONO-DI-004 nor EP3 ONO-AE-248 modified properties INaR. In PGE2 applications 1 μM produced maximal increase INaR amplitude. (1 μM)-induced GV1/2 baseline (% change G at V1/2) attenuated by either intracellular application PKA inhibitor PKI or extracellular protein kinase C staurosporine (1 μM). However, slope factor k not altered 0.01–10 μM. In addition, V1/2 staurosporine. In other series experiments, reverse transcription–polymerase chain reaction (RT–PCR) mRNA ganglia indicated that all receptors present. The NG contained many neuronal cell bodies (diameter <30 μm) intense moderate EP2, EP3, receptor-immunoreactivities. These results suggest PGE2-induced is mainly mediated both receptors. Keywords: Prostaglandin E2, tetrodotoxin-resistant, receptor, ganglion, RT–PCR, immunohistochemistry Introduction It has been demonstrated prostaglandin E2 (PGE2), one hyperalgesic agents, enhances responsiveness primary nociceptive neurones bradykinin and/or capsaicin (Nicol & Cui, 1994; Cui Nicol, 1995). Capsaicin-sensitive neurons dorsal root (DRG) preferentially express as tetrodotoxin (TTX)-resistant voltage-gated (INaR), compared case capsaicin-insensitive (Pearce Duchen, Arbuckle Docherty, expressing sensory neurone specific TTX-R channels, shifts curve more negative potentials amplitude (England et al., 1996; Gold 1998). These changes play an important role determining excitability neurones. Electrophysiological currents resemble those putative 1 referred slow well NaV 1.8 (Rush 1998; Scholz Lai 2002). The known contain neurones, receive afferent inputs cardiovascular, pulmonary, gastrointestinal tracts. majority have conduction velocity (C type neurons) consistent unmyelinated axons (Stansfeld Wallis, 1985). During inflammatory airways, autacoids, including prostaglandins, are locally released variety cells, particularly abundant prostanoid found lungs airways during inflammation. latter confirmed evidence demonstrating asthmatic attack human patients, levels bronchoalveolar lavage two- 10-fold, before (Liu 1988; Holtzman, 1991; Jorres Furthermore, potentiating effect sensitivity vagal fiber activity response chemical mechanical stimulation (Lee Morton, 1995; Ho 2000). The multiformity thought be responsible for subtypes, EP1–EP4, coupled different signal transduction pathways (Narumiya 1999). DRG neurons, sensitizing A (PKA) transduction, involved (Lopshire Southall Vasko, 2001). linked adenylate cyclase through Gs 1999), effects occur result cAMP-PKA mechanism, indicating may (Cui Lopshire Smith 2000). it how agonists, exhibiting highest affinity (Coleman Narumiya modify insensitive TTX. determine We therefore examined selective concentrations (0.01–10 μM) expression means (RT–PCR). Finally, we actually expressed small-diameter using antibodies.