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Target Concepts:
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Query: UNIPROT:P20366 (
substance P
)
21,176
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Low-voltage-activated T-type Ca(2+) channels (T-channels), especially Cav3.2 among the three isoforms (
Cav3.1
, Cav3.2, and Cav3.3), are now considered to play pivotal roles in processing of pain signals. Cav3.2 T-channels are functionally modulated by extracellular substances such as hydrogen sulfide and ascorbic acid, by intracellular signaling molecules including protein kinases, and by glycosylation. Cav3.2 T-channels are abundantly expressed in both peripheral and central endings of the primary afferent neurons, regulating neuronal excitability and release of excitatory neurotransmitters such as
substance P
and glutamate, respectively. Functional upregulation of Cav3.2 T-channels is involved in the pathophysiology of inflammatory, neuropathic, and visceral pain. Thus, Cav3.2 T-channels are considered to serve as novel targets for development of drugs for treatment of intractable pain resistant to currently available analgesics.
...
PMID:T-type calcium channels: functional regulation and implication in pain signaling. 2390 7
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
