Thapsigargin-induced activation of Ca2+-CaMKII-ERK in brainstem contributes to substance P release and induction of emesis in the least shrew

Zhong, Weixia; Chebolu, Seetha; Darmani, Nissar A.

doi:10.1016/j.neuropharm.2015.11.023

Cited by 37 publications

(104 citation statements)

References 73 publications

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“…Our lab has well described the circumventricular organ AP and the different cytoarchitectonic detail such as cell size and packing differentiating DMNX from NTS within the DVC, as part of a stereotaxic atlas of the least shrew brainstem (Ray et al, 2009a). This criterion has been well recognized (Chebolu et al, 2010; Darmani et al, 2008; Ray et al, 2009a and 2009c; Zhong et al, 2014b and 2016). …”

Section: Methodsmentioning

confidence: 93%

“…Thapsigargin is also a potent emetogen since it evokes robust vomiting in least shrews and increases c-Fos expression in brainstem emetic nuclei AP, NTS and DMNX, as well as SP immunoreactivity in DMNX (Zhong et al, 2016). Ca 2+ release from intracellular sarcoplasmic/endoplasmic reticulum (SER) into cytoplasm is accomplished by inositol trisphosphate receptors (IP 3 Rs) and ryanodine receptors (RyRs) (Gomez-Viquez et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Ca 2+ release from intracellular sarcoplasmic/endoplasmic reticulum (SER) into cytoplasm is accomplished by inositol trisphosphate receptors (IP 3 Rs) and ryanodine receptors (RyRs) (Gomez-Viquez et al, 2003). IP 3 Rs and RyRs are differentially involved in vomiting evoked by different emetogens (Zhong et al, 2014b and 2016). Thapsigargin- and FPL64176-like drugs affecting cytosolic Ca 2+ dynamics are considered as potential targeted apoptotic chemotherapeutics (Cano-Abad et al, 2001; Doan et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Vomit-associated cytosolic Ca 2+ rise as well as time-dependent increases in phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) occur in the shrew brainstem following 5-HT 3 R-mediated vomiting and emesis caused by thapsigargin (Zhong et al, 2014b and 2016). Moreover, protein kinase Cα/βII (PKCα/βII) and ERK1/2 phosphorylation have been observed during cisplatin-induced emesis (Darmani et al, 2013 and 2015).…”

Section: Introductionmentioning

confidence: 99%

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Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

Zhong

Chebolu

Darmani

2018

European Journal of Pharmacology

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Ca2+ plays a major role in maintaining cellular homeostasis and regulates processes including apoptotic cell death and side-effects of cancer chemotherapy including vomiting. Currently we explored the emetic mechanisms of FPL64176, an L-type Ca2+ channel (LTCC) agonist with maximal emetogenic effect at its 10 mg/kg dose. FPL64176 evoked c-Fos immunoreactivity in shrew brainstem sections containing the vomit-associated nuclei, nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus. FPL64176 also increased phosphorylation of proteins ERK1/2, PKCα/βII and Akt in the brainstem. Moreover, their corresponding inhibitors (PD98059, GF 109203X and LY294002, respectively) reduced FPL64176-evoked vomiting. A 30 min subcutaneous (s.c.) pretreatment with the LTCC antagonist nifedipine (10 mg/kg) abolished FPL64176-elicited vomiting, c-Fos expression, and emetic effector phosphorylation. Ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP3Rs) mediate intracellular Ca2+ release from the sarcoplasmic/endoplasmic reticulum. The RyR antagonist dantrolene (i.p.), or a combination of low doses of nifedipine and dantrolene, but not the IP3R antagonist 2-APB, significantly attenuated FPL64176-induced vomiting. The serotonin type 3 receptor (5-HT3R) antagonist palonosetron (s.c.), the neurokinin 1 receptor (NK1R) antagonist netupitant (i.p.) or a combination of non-effective doses of netupitant and palonosetron showed antiemetic potential against FPL64176-evoked vomiting. Serotonin (5-HT) and substance P immunostaining revealed FPL64176-induced emesis was accompanied by an increase in 5-HT but not SP-immunoreactivity in the dorsomedial subdivision of the NTS. These findings demonstrate that Ca2+ mobilization through LTCCs and RyRs, and subsequent emetic effector phosphorylation and 5-HT release play important roles in FPL64176-induced emesis which can be prevented by 5-HT3R and NK1R antagonists.

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Section: Methodsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

Zhong

Chebolu

Darmani

2018

European Journal of Pharmacology

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“…70 In addition, pharmacological elevation of intracellular Ca 2+ by systemic thapsigargin administration (0.5 mg/kg, i.p.) can also activate the emeticCaMKII-ERK1/2 signaling in the shrew brainstem 76 ( Figure 2). Further support for the involvement of CaMKII-ERK1/2 pathway in thapsigargin-evoked vomiting comes from the ability of their specific inhibitors (KN93 and PD98059, respectively) to suppress the induced vomiting in a manner similar to the discussed pathway for the 2-Me-5-HT-induced vomiting.…”

Section: + -Related Signaling Pathway In Emesis Camp-pkamentioning

confidence: 99%

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

Darmani

Zhong²

2015

Gastro Open J

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Citation-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-HT 3 (e.g. 5-HT or 2-Me-5-HT)-, NK 1 (GR73632)-, D 2 (apomorphine or quinpirole)-, and M 1 (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 Ca 2+ channels in neurons. In this review, we will examine the current knowledge on the role of Ca 2+ channels and Ca 2+-dependent signaling pathways in the perception and modulation of emesis.

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Management of nutritional and gastrointestinal issues in RASopathies: A narrative review

Onesimo

Giorgio

Viscogliosi

et al. 2022

American J of Med Genetics Pt C

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Noonan, Costello, and cardio-facio-cutaneous syndrome are neurodevelopmental disorders belonging to the RASopathies, a group of syndromes caused by alterations in the RAS/MAPK pathway. They are characterized by similar clinical features, among which feeding difficulties, growth delay, and gastro-intestinal disorders are frequent, causing pain and discomfort in patients. Hereby, we describe the main nutritional and gastrointestinal issues reported in individuals with RASopathies, specifically in Noonan syndrome, Noonan syndrome-related disorders, Costello, and cardio-faciocutaneous syndromes. Fifty percent of children with Noonan syndrome may experience feeding difficulties that usually have a spontaneous resolution by the second year of life, especially associated to genes different than PTPN11 and SOS1. More severe manifestations often require artificial enteral nutrition in infancy are observed in Costello syndrome, mostly associated to c.34G>A substitution in the HRAS gene.In cardio-facio-cutaneous syndrome feeding issues are usually present (90-100% of cases), especially in individuals carrying variants in BRAF, MAP2K1, and MAP2K2 genes, and artificial enteral intervention, even after scholar age, may be required.Moreover, disorders associated with gastrointestinal dysmotility as gastroesophageal reflux and constipation are commonly reported in all the abovementioned syndromes. Given the impact on growth and on the quality of life of these patients, early evaluation and prompt personalized management plans are fundamental.

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Thapsigargin-induced activation of Ca2+-CaMKII-ERK in brainstem contributes to substance P release and induction of emesis in the least shrew

Cited by 37 publications

References 73 publications

Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

Intracellular emetic signaling evoked by the L-type Ca2+ channel agonist FPL64176 in the least shrew (Cryptotis parva)

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

Management of nutritional and gastrointestinal issues in RASopathies: A narrative review

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