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.