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L‐Type Calcium Channels Contribute to 5‐HT3‐Receptor‐Evoked CaMKIIα and ERK Activation and Induction of Emesis in the Least Shrew ( Cryptotis parva )
Author(s) -
Darmani Nissar,
Hutchinson Tarun,
Zhong Weixia,
Chebolu Seetha
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.628.2
Subject(s) - chemistry , nifedipine , endocrinology , medicine , calcium in biology , pharmacology , calcium , intracellular , biology , biochemistry , organic chemistry
5‐HT 3 receptor (5‐HT 3 Rs) activation by 2‐methyl serotonin (2‐Me‐5‐HT) induces vomiting which is sensitive to antagonists of 5‐HT 3 Rs (palonosetron) and L‐type calcium channels (LTCC) (amlodipine or nifedipine). Previously we had demonstrated that 5‐HT 3 R activation causes increases in a palonosetron‐sensitive manner, in: i) intracellular Ca 2+ concentration, ii) attachment of calmodulin (CaM) to 5‐HT 3 R, and iii) phosphorylation of CaMKIIα and ERK1/2. Here, we investigate the role of nifedipine on 2‐Me‐5‐HT‐evoked intracellular Ca 2+ increase and on downstream intracellular emetic signaling. We present evidence for the contribution of Ca 2+ influx through LTCCs (sensitive to nifedipine) in 2‐Me‐5‐HT (1 µM) ‐evoked rise in cytosolic Ca 2+ levels in least shrew brainstem slices. Nifedipine pretreatment (10 mg/kg) also suppressed 2‐Me‐5‐HT‐evoked interaction of 5‐HT3Rs with CaM as well as phosphorylation of CaMKIIα and ERK1/2 in the least shrew brainstem, and 5‐HT 3 Rs‐CaM colocalization in jejunum. In vitro exposure of isolated enterochromaffin cells to 2‐Me‐5‐HT (1 µM) caused CaMKIIα phosphorylation, which was also abrogated by nifedipine pretreatment (0.1 µM). Pretreatment with the CaMKII inhibitor KN62 (10 mg/kg, i.p.) suppressed emesis and also the activation of CaMKIIα, and ERK in brainstem caused by 2‐Me‐5‐HT (5 mg/kg). This study provides mechanistic explanation for our published findings that nifedipine can protect shrews from 2‐Me‐5‐HT‐induced vomiting.