Chapters authored
Role of Calcium in Vomiting
Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca2+)-dependent release of multiple neurotransmitters/mediators (dopamine, serotonin, substance P, prostaglandins and leukotrienes) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca2+ signaling is triggered by activation of diverse emetic receptors (including neurokininergic NK1, serotonergic 5-HT3, dopaminergic D2, cholinergic M1, or histaminergic H1), whose stimulation in vomit-competent species evokes emesis. Other emetogens such as cisplatin, rotavirus NSP4 protein, and bacterial toxins can also induce intracellular Ca2+ elevation. Our findings demonstrate that application of the L-type Ca2+ channel (LTCC) agonist FPL 64176 and the intracellular Ca2+ mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor) cause vomiting in the least shrew. On the other hand, blockade of LTCCs by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic efficacy against diverse agents that specifically activate emetogenic receptors such as 5-HT3, NK1, D2, and M1 receptors, but can also potentiate the antiemetic efficacy of palonosetron against the nonspecific emetogen, cisplatin. In this review, we will provide an overview of Ca2+ involvement in the emetic process; discuss the relationship between Ca2+ signaling and the prevailing therapeutics in control of vomiting; highlight the current evidence for Ca2+-signaling blockers/inhibitors in suppressing emetic behavior and also draw attention to the clinical benefits of Ca2+-signaling blockers/inhibitors for the treatment of nausea and vomiting.
Part of the book: Calcium and Signal Transduction