Role of Calcium in Vomiting: Revelations from the Least Shrew Model of Emesis
DOI:
https://doi.org/10.17140/GOJ-1-121Keywords:
Calcium, Cisplatin, 5-HT3 receptor, L-type Ca2+ channel, Ryanodine receptor, Signaling pathwayAbstract
Cisplatin-like chemotherapeutics cause vomiting via release of multiple neurotransmitters (dopamine, serotonin, or substance P) from the gastrointestinal enterochromaffin cells and/or the brainstem via a Calcium (Ca2+) dependent process. In addition, evidence from literature indicate that Ca2 + signaling is also triggered subsequent to activation of other emetogenic receptors including serotonergic 5-HT3, tachykinin NK1, dopamine D2, and histaminergic H1 receptors. Moreover, other emetogens such as prostaglandins, cisplatin, rotavirus NSP4 protein and bacterial toxins have the ability to induce intracellular Ca2 + elevation. Our findings demonstrate that application of the L-type Ca2+ channel (LTCC) agonist FPL-64176 or the Ca2+ mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor) cause vomiting in the least shrew, whereas blockade of LTCC by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic activity against diverse emetogens including agonists of 5-HT3
(e.g. 5-HT or 2-Me-5-HT)-, NK1 (GR73632)-, D2 (apomorphine or quinpirole)-, and M1 (McN-A343)-receptors, but can also potentiate the antiemetic efficacy of well-established antiemetic palonosetron against the non-specific emetogen, cisplatin. The transmission of emesis signals in the gastrointestinal tract and brainstem is crucially dependent on Ca2+ channels in neurons. In this review, we will examine the current knowledge on the role of Ca2+ channels and Ca2+-dependent signaling pathways in the perception and modulation of emesis.
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