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The TRPV1: a possible role in GERD, asthma and migraine
Author(s) -
Geppetti P.
Publication year - 2004
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/j.0906-6705.2004.00212q.x
Subject(s) - trpv1 , capsazepine , chemistry , calcitonin gene related peptide , transient receptor potential channel , capsaicin , receptor , endocrinology , substance p , pharmacology , medicine , microbiology and biotechnology , biochemistry , neuropeptide , biology
The transient receptor potential vanilloid type 1 (TRPV1) is a non‐selective ion channel that belongs to the TRP family of channels that are activated by vanilloid molecules, including capsaicin. The cloned TRPV1 is a thermosensor, gated by temperature (43–52°C) and low pH. Additional putative endogenous activators of the TRPV1 are the cannabinoid receptor agonist, anandamide, N ‐arachydonoil‐dopamine and certain lipoxigenase metabolites of arachidonic acid, as 12‐HPETE and LTB4. The TRPV1 is expressed selectively in a subpopulation of primary sensory neurons with C‐ and A‐delta fibres which also express NGF receptors, the neuropeptides, substance P (SP), neurokinin A and calcitonin gene‐related peptide (CGRP). These neurons being activated by different sensory (mechanichal, thermal and chemical) modalities are defined as polymodal nociceptors, and the peptides released from their peripheral terminals cause neurogenic inflammation. TRPV1 seems to be coupled with PLC and PIP2 hydrolysis results in channel activation. Additional modes of TRPV1 sensitization comprise PKC‐ and PKA‐dependent pathways. Activation of either G‐protein‐coupled receptors or tyrosine kinase receptors causes TRPV1 sensitization. Of pathophysiological interest is the finding that endogenous and exogenous molecules may also cause TRPV1. Recently, we found that exposure to 0.3–3% ethanol causes a remarkable increase in Ca 2+ mobilization in capsaicin‐sensitive cultured DRG neurons of newborn rat, an effect that was inhibited by the TRPV1 antagonist capsazepine. Wild‐type human embryonic kidney (HEK) cells did not respond to ethanol, but transfection with the human TRPV1 conferred to these cells the ability to respond to ethanol (Ca 2+ mobilization) in a capsazepine‐sensitive manner. Electrophysiological studies showed that ethanol dramatically potentiated currents activated by anandamide and protons, and that ethanol reduced the threshold temperature for TRPV1 activation by about 8°C. Thus, in the presence of ethanol, the physiological temperature of 37°C is a sufficient stimulus to activate TRPV1 on sensory neurons and activate their afferent and efferent functions. Ethanol can trigger attacks of asthma and migraine and aggravates the symptoms of GERD. Exposure to ethanol caused a Ca 2+ ‐dependent release of neuropeptides (SP/CGRP) from slices of rat esophagus and dura mater and guinea‐pig airways and increased plasma extravasation in the rat oesophagus and dura mater and caused bronchoconstriction in vitro and in vivo in guinea pigs. All these responses were inhibited selectively by capsazepine. Activation of sensory neurons and neurogenic inflammatory responses via TRPV1 stimulation may contribute to the mechanism of attacks of migraine and to the worsening of GERD and asthma symptoms precipitated by alcohol ingestion.