The Journal of neuroscience : the official journal of the Society for Neuroscience
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We have identified a mechanism, mediated by the epsilon isozyme of protein kinase C (PKCepsilon) in peripheral neurons, which may have a role in chronic inflammatory pain. Acute inflammation, produced by carrageenan injection in the rat hindpaw, produced mechanical hyperalgesia that resolved by 72 hr. However, for up to 3 weeks after carrageenan, injection of the inflammatory mediators prostaglandin E(2) or 5-hydroxytryptamine or of an adenosine A(2) agonist into the same site induced a markedly prolonged hyperalgesia (>24 hr compared with 5 hr or less in control rats not pretreated with carrageenan). ⋯ Acute carrageenan hyperalgesia could be inhibited by PKA or PKG antagonists. However, these antagonists did not inhibit development of the hypersensitivity to inflammatory mediators. Our findings indicate that different second messenger pathways underlie acute and prolonged inflammatory pain.
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The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling cascade contributes to synaptic plasticity and to long-term memory formation, yet whether MAPK/ERK controls activity-dependent gene expression critical for long-lasting changes at the synapse and what the events underlying transduction of the signal are remain uncertain. Here we show that induction of long-term potentiation (LTP) in the dentate gyrus in vivo leads to rapid phosphorylation and nuclear translocation of MAPK/ERK. Following a similar time course, the two downstream transcriptional targets of MAPK/ERK, cAMP response element-binding protein (CREB) and the ternary complex factor Elk-1, a key transcriptional-regulator of serum response element (SRE)-driven gene expression, were hyperphosphorylated and the immediate early gene zif268 was upregulated. ⋯ We also show that inhibition of the MAPK/ERK cascade by the MAPK kinase MEK inhibitor SL327 prevented CREB and Elk-1 phosphorylation, and LTP-dependent gene induction, resulting in rapidly decaying LTP. In conclusion, we suggest that Elk-1 forms an important link in the MAP kinase pathway to transduce signals from the cell surface to the nucleus to activate the genetic machinery necessary for the maintenance of synaptic plasticity in the dentate gyrus. Thus, MAPK/ERK activation is required for LTP-dependent transcriptional regulation and we suggest this is regulated by two parallel signaling pathways, the MAPK/ERK-Elk-1 pathway targeting SRE and the MAPK/ERK-CREB pathway targeting CRE.
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Activation of M(1) muscarinic acetylcholine receptors (M(1) mAChR) inhibits M-type potassium currents (I(K(M))) and N-type calcium currents (I(Ca)) in mammalian sympathetic ganglia. Previous antisense experiments suggested that, in rat superior cervical ganglion (SCG) neurons, both effects were partly mediated by the G-protein Galpha(q) (Delmas et al., 1998a; Haley et al., 1998a), but did not eliminate a contribution by other pertussis toxin (PTX)-insensitive G-proteins. We have tested this further using mice deficient in the Galpha(q) gene. ⋯ In mouse SCG neurons, I(K(M)) inhibition by BK was fully PTX-resistant. It was unchanged in Galpha(q) -/- mice but was abolished by anti-Galpha(q/11) antibody. We conclude that, in mouse SCG neurons (1) M(1) mAChR inhibition of I(Ca) is mediated principally by G(q), (2) M(1) mAChR inhibition of I(K(M)) is mediated partly by G(q), more substantially by G(11), and partly by a PTX-sensitive G-protein(s), and (3) BK-induced inhibition of I(K(M)) is mediated wholly by G(11).