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: UMLS:C0002736 (
amyotrophic lateral sclerosis
)
19,048
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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
