Analgesic compound from sea anemone Heteractis crispa is the first polypeptide inhibitor of vanilloid receptor 1 (TRPV1).
Venomous animals from distinct phyla such as spiders, scorpions, snakes, cone snails, or sea anemones produce small toxic proteins interacting with a variety of cell targets. Their bites often cause pain. One of the ways of pain generation is the activation of TRPV1 channels. Screening of 30 different venoms from spiders and sea anemones for modulation of TRPV1 activity revealed inhibitors in tropical sea anemone Heteractis crispa venom. Several separation steps resulted in isolation of an inhibiting compound. This is a 56-residue-long polypeptide named APHC1 that has a Bos taurus trypsin inhibitor (BPTI)/Kunitz-type fold, mostly represented by serine protease inhibitors and ion channel blockers. APHC1 acted as a partial antagonist of capsaicin-induced currents (32 +/- 9% inhibition) with half-maximal effective concentration (EC(50)) 54 +/- 4 nm. In vivo, a 0.1 mg/kg dose of APHC1 significantly prolonged tail-flick latency and reduced capsaicin-induced acute pain. Therefore, our results can make an important contribution to the research into molecular mechanisms of TRPV1 modulation and help to solve the problem of overactivity of this receptor during a number of pathological processes in the organism.
Andreev
Yaroslav A
YA
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow. ay@land.ru
Kozlov
Sergey A
SA
Koshelev
Sergey G
SG
Ivanova
Ekaterina A
EA
Monastyrnaya
Margarita M
MM
Kozlovskaya
Emma P
EP
Grishin
Eugene V
EV
D000700:Analgesics / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D007611:Aprotinin; D001483:Base Sequence; D002211:Capsaicin / Q000494:pharmacology; D002415:Cats; D003064:Cnidarian Venoms / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009865:Oocytes; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010455:Peptides / Q000302:isolation & purification / Q000494:pharmacology*; D017510:Protein Folding; D012615:Sea Anemones; D018689:Sensory System Agents / Q000494:pharmacology; D040681:Structural Homology, Protein; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014982:Xenopus laevis
D000700:Analgesics; D003064:Cnidarian Venoms; D010455:Peptides; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C577093:analgesic polypeptide HC1, Heteractis crispa; D007611:Aprotinin; D002211:Capsaicin