Role of Calcium in Vomiting: Revelations from the Least Shrew Model of Emesis

Abstract

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.