Gastro · Vol. 1, No. 5 · 2015 · pp. 119–128 · e-ISSN 2377-8369

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

Nissar A. Darmani, Weixia Zhong

Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, West - ern University of Health Sciences, Pomona, CA 91766, USAUnited States

DOI: https://doi.org/10.17140/goj-1-121 · Published 2015-12-28 · Licence: https://creativecommons.org/licenses/by/4.0 · © 2015 The Author(s)

Also available as PDF (figures and tables appear in the PDF).

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.

Keywords: Calcium; Cisplatin; 5-HT3 receptor; L-type Ca2+ channel; Ryanodine receptor; Signaling pathway

Conclusion

pathway for selective 5-HT3R agonist 2-Me-5-HT in the least

shrew. As shown in Figure 3, we have proposed that following In this review, we have discussed: 1) the transmission

2+ 5-HT3R activation, the enhanced Ca2+ mobilization is also seof emetic signals at the brainstem level is crucially dependent

2+ quentially linked to the intracellular activation of the CaMKIIon Ca2+ channels located on plasma membrane and intracellular

2+ ERK1/2 pathway in the brainstem, which plays an important role Ca2+ stores in the SER; 2) the implications of these findings for

in 2-Me-5-HT-induced vomiting.70 In addition, pharmacological the design of novel therapeutic strategies and have compared

2+ 2+ elevation of intracellular Ca2+ by systemic thapsigargin adminthe role of L-type Ca2+ channels antagonists nifedipine with

2+ istration (0.5 mg/kg, i.p.) can also activate the emeticCaMKIIamlodipine in emesis management; and 3) the Ca2+-mediated

ERK1/2 signaling in the shrew brainstem76 (Figure 2). Further signaling transduction pathway in the brainstem involved in di-

support for the involvement of CaMKII-ERK1/2 pathway in verse emetogens-evoked vomiting. We envisage development

thapsigargin-evoked vomiting comes from the ability of their of universal antiemetics can be possible if one targets: i) one

critical step in each of the few available post-receptor emetic 10. Aman TK, Shen RY, Haj-Dahmane S. D2-like dopamine re-

signal transduction systems which the above-discussed diverse ceptors depolarize dorsal raphe serotonin neurons through the

emetogens share downstream of their corresponding receptors, activation of nonselective cationic conductance. J Pharmacol

or ii) a common essential signal which can cross-talk between Exp Therap. 2007; 320: 376-385. doi: 10.1124/jpet.106.111690

2+ these transduction pathways such as, Ca2+.

11. Wu J, Dougherty JJ, Nichols RA. Dopamine receptor regula-

2+

Conflicts Of Interests

tion of Ca2+ levels in individual isolated nerve terminals from rat

striatum: comparison of presynaptic D1-like and D2-like recep-

The authors declare that they have no conflicts of interest. tors. J Neuroscience. 2006; 98: 481-494.

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