Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.1.4.3 (
phospholipase C
)
18,461
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Management of pain by opioid analgesics is confounded by central adverse effects that limit clinical dosages. Consequently, there is considerable interest to understand peripheral analgesic effects of opioids. The actions of opioids on peripheral sensory neurons have been difficult to study because of a general lack of effect of opioid agonists on nociceptor function in culture despite documented presence of opioid receptors. In this study, the micro-opioid receptor agonist, [D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin (DAMGO), did not alter guanosine 5'-O-(3-[(35)S]thio)-triphosphate (GTPgamma[(35)S]) binding, adenylyl cyclase activity, or neuropeptide release in primary cultures of rat trigeminal ganglion (TG). However, after brief exposure to bradykinin (BK), DAMGO stimulated GTPgamma[(35)S] binding and inhibited both prostaglandin E(2) (PGE(2))-stimulated adenylyl cyclase activity and BK/PGE(2)-stimulated neuropeptide release. The effect of BK was blocked by the B(2) antagonist HOE 140 [D-Arg[Hyp(3),Thi(5),D-
Tic
(7),Oic(8)]-bradykinin], but not by the B(1) antagonist, Lys-[Leu8]des-Arg9-BK, and was mimicked by the protease-activated receptor-2 agonist, Ser-Leu-Ile-Gly-Arg-Leu-NH(2), and by activation of protein kinase C (PKC) or by administration of arachidonic acid (AA). The enhanced responsiveness of micro-opioid receptor signaling by BK priming was blocked by both cyclooxygenase and PKC inhibitors; however, the effect of AA was blocked only by a cyclooxygenase inhibitor. The results indicate that micro-opioid receptor signaling in primary sensory TG neurons is enhanced by activation of
phospholipase C
-coupled receptors via a cyclooxygenase-dependent AA metabolite that is downstream of PKC.
...
PMID:Rapid modulation of micro-opioid receptor signaling in primary sensory neurons. 1734 22
Bradykinin (BK), a hormone inducing pain and inflammation, is known to inhibit potassium M-currents (I
M
) and to increase the excitability of the superior cervical ganglion (SCG) neurons by activating the Ca
2+
-calmodulin pathway. M-current is also reduced by muscarinic agonists through the depletion of membrane phosphatidylinositol 4,5-biphosphate (PIP
2
). Similarly, the activation of muscarinic receptors inhibits the current through two-pore domain potassium channels (K2P) of the "Tandem of pore-domains in a Weakly Inward rectifying K
+
channel (TWIK)-related channels" (TREK) subfamily by reducing PIP
2
in mouse SCG neurons (mSCG). The aim of this work was to test and characterize the modulation of TREK channels by bradykinin. We used the perforated-patch technique to investigate riluzole (RIL) activated currents in voltage- and current-clamp experiments. RIL is a drug used in the palliative treatment of amyotrophic lateral sclerosis and, in addition to blocking voltage-dependent sodium channels, it also selectively activates the K2P channels of the TREK subfamily. A cell-attached patch-clamp was also used to investigate TREK-2 single channel currents. We report here that BK reduces spike frequency adaptation (SFA), inhibits the riluzole-activated current (I
RIL
), which flows mainly through TREK-2 channels, by about 45%, and reduces the open probability of identified single TREK-2 channels in cultured mSCG cells. The effect of BK on I
RIL
was precluded by the bradykinin receptor (B
2
R) antagonist HOE-140 (d-Arg-[Hyp
3
, Thi
5
, d-
Tic
7
, Oic
8
]BK) but also by diC
8
PIP
2
which prevents PIP
2
depletion when
phospholipase C
(
PLC
) is activated. On the contrary, antagonizing inositol triphosphate receptors (IP
3
R) using 2-aminoethoxydiphenylborane (2-APB) or inhibiting protein kinase C (PKC) with bisindolylmaleimide did not affect the inhibition of I
RIL
by BK. In conclusion, bradykinin inhibits TREK-2 channels through the activation of B
2
Rs resulting in PIP
2
depletion, much like we have demonstrated for muscarinic agonists. This mechanism implies that TREK channels must be relevant for the capture of information about pain and visceral inflammation.
...
PMID:PIP
2
Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons. 3193 57
