**Calcium Signaling and Physiologic Consequences in Chemotherapeutic and Cancer Pathology**

[93] Yonekawa T, Ohnishi Y, Horinouchi S. A calcium-binding protein with four EF-hand motifs in *Streptomyces ambofaciens*. Bioscience, Biotechnology, and Biochemistry.

[94] Pace J, Hayman MJ, Galan JE. Signal transduction and invasion of epithelial cells by *S.* 

[95] Gekara NO et al. The multiple mechanisms of Ca2+ signalling by listeriolysin O, the cholesterol-dependent cytolysin of *Listeria monocytogenes*. Cellular Microbiology.

[96] Johnson MD et al. *Pseudomonas aeruginosa* PilY1 binds integrin in an RGD- and calcium-

[97] Hu L, Raybourne RB, Kopecko DJ. Ca2+ release from host intracellular stores and related signal transduction during *Campylobacter jejuni* 81-176 internalization into human intes-

[98] Grab DJ et al. Human brain microvascular endothelial cell traversal by *Borrelia burgdorferi* requires calcium signaling. Clinical Microbiology and Infection. 2009;**15**(5):422-426

[99] Bonnet M, Nhieu GTV. How Shigella utilizes Ca2+ jagged edge signals during invasion of epithelial cells. Frontiers in Cellular and Infection Microbiology. 2016;**6**:16. 1-8 [100] Flotho A, Melchior F. Sumoylation: A regulatory protein modification in health and

[101] Lapaquette P et al. Shigella entry unveils a calcium/calpain-dependent mechanism for

[102] Reboud E et al. *Pseudomonas aeruginosa* ExlA and *Serratia marcescens* ShlA trigger cadherin cleavage by promoting calcium influx and ADAM10 activation. PLoS Pathogens.

[103] Repp H et al. Listeriolysin of *Listeria monocytogenes* forms Ca2+-permeable pores leading

to intracellular Ca2+ oscillations. Cellular Microbiology. 2002;**4**(8):483-491

2001;**65**(1):156-160

106 Calcium and Signal Transduction

2007;**9**(8):2008-2021

2017;**13**(8):e1006579

*typhimurium*. Cell. 1993;**72**(4):505-514

dependent manner. PLoS One. 2011;**6**(12):e29629

tinal cells. Microbiology. 2005;**151**(Pt 9):3097-3105

disease. Annual Review of Biochemistry. 2013;**82**:357-385

inhibiting sumoylation. eLife. 2017;**6**:e27444. 1-24

**Chapter 6**

**Provisional chapter**

, cholinergic

, NK<sup>1</sup> , D<sup>2</sup> ,

**Role of Calcium in Vomiting**

**Role of Calcium in Vomiting**

Weixia Zhong and Nissar A. Darmani

Weixia Zhong and Nissar A. Darmani

http://dx.doi.org/10.5772/intechopen.78370

tors (including neurokininergic NK1

) ,

, or histaminergic H<sup>1</sup>

**Abstract**

M1

and M1

vomiting.

**1. Introduction**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

DOI: 10.5772/intechopen.78370

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 recep-

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-HT<sup>3</sup>

**Keywords:** cisplatin, vomiting, antiemesis, Ca2+, L-type Ca2+ channel

, serotonergic 5-HT<sup>3</sup>

 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

Acute (≤24 h) and delayed (>24 h) phases of chemotherapy-induced nausea and vomiting cause distressing side-effects which affect the well-being and quality of life of cancer patients

, dopaminergic D<sup>2</sup>

whose stimulation in vomit-competent species evokes emesis.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

#### **Chapter 6 Provisional chapter**

#### **Role of Calcium in Vomiting Role of Calcium in Vomiting**

Weixia Zhong and Nissar A. Darmani Weixia Zhong and Nissar A. Darmani

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.78370

#### **Abstract**

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-HT<sup>3</sup> , dopaminergic D<sup>2</sup> , cholinergic M1 , or histaminergic H<sup>1</sup> ) , 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-HT<sup>3</sup> , NK<sup>1</sup> , D<sup>2</sup> , 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.

DOI: 10.5772/intechopen.78370

**Keywords:** cisplatin, vomiting, antiemesis, Ca2+, L-type Ca2+ channel

#### **1. Introduction**

Acute (≤24 h) and delayed (>24 h) phases of chemotherapy-induced nausea and vomiting cause distressing side-effects which affect the well-being and quality of life of cancer patients

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

receiving chemotherapy, especially cisplatin [1]. Major neurotransmitter mechanisms underlying chemotherapy-induced nausea and vomiting have been subject of considerable research over the past 45 years. As presented in brief in **Figure 1**, cancer chemotherapeutics such as cisplatin evoke vomiting via local release of a variety of emetic neurotransmitters/mediators (including dopamine, serotonin (5-HT), substance P, prostaglandins and leukotrienes) both from the enterochromaffin cells of the gastrointestinal tract and the brainstem emetic loci in the dorsal vagal complex containing the nucleus tractus solitarius, the dorsal motor nucleus of the vagus and the area postrema [2–4]. The area postrema and the nucleus tractus solitarius contain large numbers of fenestrated capillaries which lack blood-brain barrier and permit neurons in both areas access to blood-borne circulating factors including emetogens [5]. The chemoreceptor trigger zone, in the area postrema has high concentrations of emetic receptors for serotonin (5-HT<sup>3</sup> ), dopamine (D2/3), neurokinin (NK<sup>1</sup> ), and opioids (μ), among others [2]. Direct stimulation of these receptors in the chemoreceptor trigger zone by emetogens is one important mechanism by which vomiting can occur [6]. The nucleus tractus solitarius receives emesis-related information from the area postrema as well as the gastrointestinal tract conveyed by vagal afferents. The dorsal motor nucleus of the vagus receives axonal projections from nucleus tractus solitarius [7] and sends emetic signals via motor efferent pathways to the gastrointestinal tract and modulates vomiting behaviors [2, 5, 8, 9] (**Figure 1**). In addition, chemotherapeutic drugs may evoke release of emetic neurotransmitters/mediators from the gastrointestinal tract into the blood to be directly delivered to the area postrema via a

blood-borne pathway which then triggers vomiting [2, 10], and/or the released emetic neurotransmitters/mediators stimulate their corresponding receptors present on vagal afferents in the gastrointestinal tract which indirectly activate brainstem emetic loci primarily in the

signaling [160–166]. In the least shrew emesis model, the RyRs antagonist dantrolene can potentiate the antiemetic

R antagonist 2-APB can potentiate the antiemetic efficacy of nifedipine against thapsigargin-induced vomiting [70].

**Figure 2.** Overview of evidence for suppression of Ca2+ signaling involved in anti-vomiting actions of antiemetic agents.

treat the acute- and delayed- phases of chemotherapy-induced nausea and vomiting (CINV) in cancer patients [79–82]. Our studies [83–86] indicate that suppression of Ca2+ signaling is involved in antiemetic efficacy of both palonosetron and netupitant. (2) Cannabinoids such as delta-9-tetrahydrocannabinol exert their antiemetic efficacy via direct

[111–115] and intracellular Ca2+ release from the sarco/endoplasmic reticulum stores [15, 117], result in inhibition of Ca2+-dependent neurotransmitter release [108] and is probably the fundamental mechanisms underlying the antiemetic

acute and delayed CINV [6]. Glucocorticoids' ability to decrease the abnormal elevation of cytosolic Ca2+ concentration [122], and subsequently control Ca2+-dependent neurotransmitter release [6, 121, 126] and inflammatory responses [6].

glucocorticoids [123–125]. (4) The L-type Ca2+ channel (LTCC) antagonist flunarizine can reduce cyclic vomiting in patients [151, 152]. Gabapentin binds to the alpha-2/delta auxiliary subunits of LTCCs, and exerts inhibitory actions on trafficking and activation kinetics of LTCCs [153]. Gabapentin can be used as an anti-nausea and antiemetic agent in postoperative nausea and vomiting [154, 155] and in CINV [156, 157]. (5) LTCC antagonists (nifedipine and amlodipine) are broad-spectrum antiemetics when delivered systemically against diverse specific and nonselective emetogens. (6) Suppression of intracellular Ca2+ release from the sarco/endoplasmic reticulum through the inositol trisphosphate

R cannabinoid agonists against CINV [95–97]. (3) Glucocorticoids such as dexamethasone reduce both

Rs) and ryanodine receptors (RyRs) may be additional targets for the prevention of nausea and vomiting,

R agonist 2-Methyl-5-HT-induced vomiting [25]; and dantrolene together with the

Rs and 5-HT<sup>3</sup>

R agonists to suppress both extracellular Ca2+ influx

R activation may also be involved in antiemetic actions of

Rs are approved to

Role of Calcium in Vomiting

111

http://dx.doi.org/10.5772/intechopen.78370

Rs/RyRs play a role in Ca2+

(1) Netupitant and palonosetron are highly selective respective antagonists of NK<sup>1</sup>

R) [92, 94, 98–100]. The ability of CB<sup>1</sup>

since functional and physical linkages between Ca2+ channels on cell membrane and IP<sup>3</sup>

Ca2+ is not only one of the most universal and versatile signaling molecules, it is also an extremely important factor in both the physiology and pathology of living organisms. At rest, diverse cells have strict and well-regulated mechanisms to maintain low nM cytosolic Ca2+ levels [11]. Cytoplasmic Ca2+ concentration is a dominant factor in determining the amount of transmitter released from nerve terminals [12]. Thus, Ca2+ mobilization can be an important aspect of vomit induction since it is involved in both triggering the quantity of neurotransmitter released coupled with receptor activation, as well as post-receptor excitation-transcription coupling mechanisms [13]. Studies using Ca2+ imaging performed in vitro in the brainstem slice preparation suggest that emetic agents evoke direct excitatory effects on cytosolic Ca2+ signals in vagal afferent terminals in the nucleus tractus solitarius which potentiate local neurotransmitter release [5, 14, 15]. Therefore, chemotherapeutics including cisplatin seem to activate emetic circuits through a number of neurotransmitters released in a Ca2+-dependent

nucleus tractus solitaries to trigger vomiting [6].

activation of CB1

efficacy of CB<sup>1</sup>

receptors (IP<sup>3</sup>

IP3

efficacy of amlodipine against 5-HT<sup>3</sup>

receptors (CB1

Increased release of endocannabinoids and subsequent CB<sup>1</sup>

**Figure 1.** Brief illustration of the mechanisms underlying vomiting induced by chemotherapeutic agent cisplatin. Mechanisms underlying cisplatin-induced vomiting can be simplified as: (1) cisplatin can increase cytoplasmic Ca2+ level to evoke Ca2+-dependent release of emetic neurotransmitters/mediators at the brainstem emetic loci, the dorsal vagal complex, and subsequently activates diverse receptors and their corresponding signaling pathways. These emetic signals are output to the gastrointestinal tract via efferents to trigger vomiting [2, 4–9]; (2) cisplatin-induced peripheral release of neurotransmitters/mediators from the gastrointestinal tract into the blood can directly stimulate the dorsal vagal complex, activate receptors signaling pathways and trigger vomiting [2, 10]; and (3) the peripherally-released emetic neurotransmitters/mediators stimulate their corresponding receptors present on vagal afferents in the gastrointestinal tract which indirectly activate brainstem emetic nuclei and trigger vomiting [6].

#### Role of Calcium in Vomiting http://dx.doi.org/10.5772/intechopen.78370 111

receiving chemotherapy, especially cisplatin [1]. Major neurotransmitter mechanisms underlying chemotherapy-induced nausea and vomiting have been subject of considerable research over the past 45 years. As presented in brief in **Figure 1**, cancer chemotherapeutics such as cisplatin evoke vomiting via local release of a variety of emetic neurotransmitters/mediators (including dopamine, serotonin (5-HT), substance P, prostaglandins and leukotrienes) both from the enterochromaffin cells of the gastrointestinal tract and the brainstem emetic loci in the dorsal vagal complex containing the nucleus tractus solitarius, the dorsal motor nucleus of the vagus and the area postrema [2–4]. The area postrema and the nucleus tractus solitarius contain large numbers of fenestrated capillaries which lack blood-brain barrier and permit neurons in both areas access to blood-borne circulating factors including emetogens [5]. The chemoreceptor trigger zone, in the area postrema has high concentrations of emetic receptors

Direct stimulation of these receptors in the chemoreceptor trigger zone by emetogens is one important mechanism by which vomiting can occur [6]. The nucleus tractus solitarius receives emesis-related information from the area postrema as well as the gastrointestinal tract conveyed by vagal afferents. The dorsal motor nucleus of the vagus receives axonal projections from nucleus tractus solitarius [7] and sends emetic signals via motor efferent pathways to the gastrointestinal tract and modulates vomiting behaviors [2, 5, 8, 9] (**Figure 1**). In addition, chemotherapeutic drugs may evoke release of emetic neurotransmitters/mediators from the gastrointestinal tract into the blood to be directly delivered to the area postrema via a

**Figure 1.** Brief illustration of the mechanisms underlying vomiting induced by chemotherapeutic agent cisplatin. Mechanisms underlying cisplatin-induced vomiting can be simplified as: (1) cisplatin can increase cytoplasmic Ca2+ level to evoke Ca2+-dependent release of emetic neurotransmitters/mediators at the brainstem emetic loci, the dorsal vagal complex, and subsequently activates diverse receptors and their corresponding signaling pathways. These emetic signals are output to the gastrointestinal tract via efferents to trigger vomiting [2, 4–9]; (2) cisplatin-induced peripheral release of neurotransmitters/mediators from the gastrointestinal tract into the blood can directly stimulate the dorsal vagal complex, activate receptors signaling pathways and trigger vomiting [2, 10]; and (3) the peripherally-released emetic neurotransmitters/mediators stimulate their corresponding receptors present on vagal afferents in the gastrointestinal

tract which indirectly activate brainstem emetic nuclei and trigger vomiting [6].

), and opioids (μ), among others [2].

), dopamine (D2/3), neurokinin (NK<sup>1</sup>

for serotonin (5-HT<sup>3</sup>

110 Calcium and Signal Transduction

**Figure 2.** Overview of evidence for suppression of Ca2+ signaling involved in anti-vomiting actions of antiemetic agents. (1) Netupitant and palonosetron are highly selective respective antagonists of NK<sup>1</sup> Rs and 5-HT<sup>3</sup> Rs are approved to treat the acute- and delayed- phases of chemotherapy-induced nausea and vomiting (CINV) in cancer patients [79–82]. Our studies [83–86] indicate that suppression of Ca2+ signaling is involved in antiemetic efficacy of both palonosetron and netupitant. (2) Cannabinoids such as delta-9-tetrahydrocannabinol exert their antiemetic efficacy via direct activation of CB1 receptors (CB1 R) [92, 94, 98–100]. The ability of CB<sup>1</sup> R agonists to suppress both extracellular Ca2+ influx [111–115] and intracellular Ca2+ release from the sarco/endoplasmic reticulum stores [15, 117], result in inhibition of Ca2+-dependent neurotransmitter release [108] and is probably the fundamental mechanisms underlying the antiemetic efficacy of CB<sup>1</sup> R cannabinoid agonists against CINV [95–97]. (3) Glucocorticoids such as dexamethasone reduce both acute and delayed CINV [6]. Glucocorticoids' ability to decrease the abnormal elevation of cytosolic Ca2+ concentration [122], and subsequently control Ca2+-dependent neurotransmitter release [6, 121, 126] and inflammatory responses [6]. Increased release of endocannabinoids and subsequent CB<sup>1</sup> R activation may also be involved in antiemetic actions of glucocorticoids [123–125]. (4) The L-type Ca2+ channel (LTCC) antagonist flunarizine can reduce cyclic vomiting in patients [151, 152]. Gabapentin binds to the alpha-2/delta auxiliary subunits of LTCCs, and exerts inhibitory actions on trafficking and activation kinetics of LTCCs [153]. Gabapentin can be used as an anti-nausea and antiemetic agent in postoperative nausea and vomiting [154, 155] and in CINV [156, 157]. (5) LTCC antagonists (nifedipine and amlodipine) are broad-spectrum antiemetics when delivered systemically against diverse specific and nonselective emetogens. (6) Suppression of intracellular Ca2+ release from the sarco/endoplasmic reticulum through the inositol trisphosphate receptors (IP<sup>3</sup> Rs) and ryanodine receptors (RyRs) may be additional targets for the prevention of nausea and vomiting, since functional and physical linkages between Ca2+ channels on cell membrane and IP<sup>3</sup> Rs/RyRs play a role in Ca2+ signaling [160–166]. In the least shrew emesis model, the RyRs antagonist dantrolene can potentiate the antiemetic efficacy of amlodipine against 5-HT<sup>3</sup> R agonist 2-Methyl-5-HT-induced vomiting [25]; and dantrolene together with the IP3 R antagonist 2-APB can potentiate the antiemetic efficacy of nifedipine against thapsigargin-induced vomiting [70].

blood-borne pathway which then triggers vomiting [2, 10], and/or the released emetic neurotransmitters/mediators stimulate their corresponding receptors present on vagal afferents in the gastrointestinal tract which indirectly activate brainstem emetic loci primarily in the nucleus tractus solitaries to trigger vomiting [6].

Ca2+ is not only one of the most universal and versatile signaling molecules, it is also an extremely important factor in both the physiology and pathology of living organisms. At rest, diverse cells have strict and well-regulated mechanisms to maintain low nM cytosolic Ca2+ levels [11]. Cytoplasmic Ca2+ concentration is a dominant factor in determining the amount of transmitter released from nerve terminals [12]. Thus, Ca2+ mobilization can be an important aspect of vomit induction since it is involved in both triggering the quantity of neurotransmitter released coupled with receptor activation, as well as post-receptor excitation-transcription coupling mechanisms [13]. Studies using Ca2+ imaging performed in vitro in the brainstem slice preparation suggest that emetic agents evoke direct excitatory effects on cytosolic Ca2+ signals in vagal afferent terminals in the nucleus tractus solitarius which potentiate local neurotransmitter release [5, 14, 15]. Therefore, chemotherapeutics including cisplatin seem to activate emetic circuits through a number of neurotransmitters released in a Ca2+-dependent manner in specific vomit-associated neuroanatomical structures. In both the periphery and the brainstem, emetic neurotransmitters/mediators—such as acetylcholine, dopamine, 5-HT, substance P, prostaglandins, leukotrienes, and/or histamine—may act independently or in combination to evoke vomiting after cisplatin administration [16] (**Figure 1**). In this review, we focus on the current evidence supporting the significance of Ca2+ signaling in emesis generation and its relationship to antiemetic efficacy, as well as the corresponding development of potential novel antiemetic medications, as shown in brief in **Figure 2**.

both the peripherally-acting 5-HT, as well as to its central nervous system-penetrating analog, 2-Methyl-5-HT [4, 41, 42]. In our studies, incubation of least shrew brainstem slices containing the dorsal vagal complex emetic loci with 2-Methyl-5-HT, results in a rapid increase in intracellular Ca2+ concentration as reflected by an increase in fluo-4 AM fluorescence intensity

A variety of Ca2+-permeable ion-channels mediating extracellular Ca2+ influx are present in the plasma membrane. Among them are voltage-gated LTCCs, which can be activated by membrane depolarization, and serve as the principal route of Ca2+ entry in electrically excitable cells such as neurons and muscle [43, 44]. Recently we have acquired direct evidence for the proposal that Ca2+ mobilization is an important facet in the mediation of emesis. In fact we have identified the novel emetogen FPL64176 (**Figure 2**), a selective agonist of LTCCs, which causes vomiting in the least shrew in a dose-dependent manner [45, 46]. All tested shrews vomited at a 10 mg/kg dose of FPL64176 administered intraperitoneally (i.p.). LTCCs have been shown to be present in enterochromaffin cells of guinea pig and human small intestinal crypts [47]. Furthermore, in these cells FPL64176 not only can enhance cytosolic Ca2+ concentration, but also increases 5-HT release from enterochromaffin cells [47]. The latter findings may have underpinnings for the mechanisms underlying FPL64176-evoked vomiting observed in least shrew model of emesis. FPL64176 (10 mg/kg., i.p.) can cause Ca2+-dependent 5-HT release from shrew intestinal enterochromaffin cells which in turn could increase vagal afferent activity via stimulation of 5-HT<sup>3</sup>

Our most recent work has focused on the Ca2+-mobilizing agent thapsigargin (**Figure 3**), a specific and potent inhibitor of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump which transports the free cytosolic Ca2+ into the lumen of the sarco/endoplasmic reticulum to

**Figure 3.** A schematic representation of extracellular Ca2+ influx and intracellular Ca2+ release contributing to thapsigargin-elicited Ca2+ mobilization. Intracellular Ca2+ release from the sarco/endoplasmic reticulum (SER) Ca2+ stores

Ca2+ uptake from the cytoplasm into SER stores by the SER Ca2+-ATPase pump (SERCA). Thapsigargin is a specific

as well as extracellular Ca2+ entry through Ca2+ channels located in the plasma membrane including store-operated Ca2+

inhibitor of SERCA and thus enhances cytosolic levels of Ca2+, a process involving SER Ca2+ release via IP<sup>3</sup>

Rs) and ryanodine receptors (RyRs) is counter-balanced by continuous

Rs and RyRs

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**2.2. Emetic potential of Ca2+ channel activators: behavioral and** 

receptors, thereby indirectly triggering emetic signals in the brainstem [2, 48].

R antagonist)/nifedipine-sensitive manner [22, 25].

in a palonosetron (a 5-HT<sup>3</sup>

**immunohistochemical evidence**

through the inositol triphosphate receptors (IP<sup>3</sup>

channels (SOCE) and L-type Ca2+ channels (LTCCs) [49–60].
