Ca²⁺ signaling and emesis: Recent progress and new perspectives

Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca²⁺)-dependent release of multiple neurotransmitters (dopamine, serotonin, substance P, etc.) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca²⁺ signaling is triggered by activation of diverse emetic receptors (including tachykininergic NK₁, serotonergic 5-HT₃, dopaminergic D₂, cholinergic M₁, or histaminergic H₁)_, whose activation in vomit-competent species can evoke emesis. Other emetogens such as cisplatin, rotavirus NSP4 protein and bacterial toxins can also induce intracellular Ca²⁺ elevation. Netupitant is a highly selective neurokinin NK₁ receptor (NK₁R) antagonist and palonosetron is a selective second-generation serotonin 5-HT₃ receptor (5-HT₃R) antagonist with a distinct pharmacological profile. An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo(®)) with >85% antiemetic efficacy is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Cannabinoid CB₁ receptor agonists possess broad-spectrum antiemetic activity since they prevent vomiting caused by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, 5-HT₃R agonists, and D₂R agonists. 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 non-specific 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 evidence for Ca²⁺-signaling blockers/inhibitors in suppressing emetic behavior in the least shrew model of emesis as well as in the clinical setting; and also draw attention to the clinical benefits of Ca²⁺-signaling blockers/inhibitors in the treatment of nausea and vomiting.