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Query: UNIPROT:P20366 (
substance P
)
21,176
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
T-type (Cav3) Ca
2+
channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca
2+
channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1-
IS2
and IS3-IS4 loops of domain I and a cluster of extracellular cysteines in the IS1-
IS2
loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and
N
-ethylmaleimide, as well as a reactive oxygen species-producing neuropeptide,
substance P
(SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His
191
in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1-
IS2
loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1-
IS2
loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc.
...
PMID:Delineating an extracellular redox-sensitive module in T-type Ca
2+
channels. 3218 93
