| ID | 324 |
|---|---|
| Name | cAMP dependent protein kinase (protein family or complex) |
| Synonyms | Protein kinase A; cAMP dependent protein kinase; cAMP dependent protein kinases |
| ID | 332 |
|---|---|
| Name | 4-aminopyridine |
| CAS | 4-pyridinamine |
| PubMed | Abstract | RScore(About this table) |
|---|---|---|
| 18720421 | Yang TT, Wang SJ: and its human metabolite OPC14857 reduce, through a presynaptic mechanism, release in rat prefrontal cortex: possible relevance to neuroprotective interventions in schizophrenia. Synapse. 2008 Nov;62(11):804-18. is a novel atypical antipsychotic drug with neuroprotective properties. As excessive release is now considered to be part of the pathophysiology of schizophrenia, the objective of this study was to use an in vitro assay system to investigate the effect of and its human metabolite OPC14857 on the release of endogenous from isolated nerve terminals (synaptosomes), freshly prepared from rat prefrontal cortex. Both and OPC13857 potently inhibited 4-aminopyridine (4-AP)-evoked release in a concentration-dependent manner. Inhibition of release by and OPC13857 was associated with a reduction of 4AP-evoked Na+ influx and depolarization, as well as downstream elevation of cytoplasmic free concentration mediated via N- and P/Q-type voltage-dependent Ca2+ channels (VDCCs). Release induced by direct Ca2+ entry with Ca2+ ionophore (ionomycin) was unaffected by or OPC13857, indicating that the inhibitory effect of or OPC13857 is not due to directly interfering with the release process at some point subsequent to Ca2+ influx. In addition, the dopamine D2 receptor antagonist haloperidol and the 5-HT 1A receptor antagonist WAY100635 all effectively blocked the or OPC13857-mediated inhibition of 4-AP-evoked release. Moreover, or OPC13857 modulation of 4-AP-evoked release appears to involve a protein kinase A (PKA) signaling cascade, insofar as pretreatment of synaptosomes with the PKA inhibitor H89 suppressed the inhibitory effect of or OPC13857. Together, these results suggest that and its human metabolite OPC14857 inhibit release from rat prefrontocortical nerve terminals, likely by the activation of D2 and 5-HT 1A receptors, which subsequently results in the reduction of nerve terminal excitability and downstream VDCC activation through a signaling cascade involving PKA. These actions of may contribute to its neuroprotective effect in excitotoxic injury. |
1(0,0,0,1) |