Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Store-operated Ca(2+) channels (SOCs) are considered to be the principal route of Ca(2+) influx in non-excitable cells. We have previously shown that in mast cells IgE+antigen (Ag) induces a dihydropyridine (DHP)-sensitive Ca(2+) influx independently of Ca(2+) store depletion. Since the DHP receptor is the alpha subunit of L-type Ca(2+) channels (LTCCs), we examined the possible role of LTCCs in mast cell activation. Mast cells exhibited substantial expression of the alpha(1C) (Ca(V)1.2) subunit mRNA and protein on their cell surface. IgE+Ag-induced Ca(2+) influx was substantially reduced by the LTCC inhibitor nifedipine, and enhanced by the LTCC activator (S)-BayK8644, whereas these agents had minimal effects on thapsigargin (TG)-induced Ca(2+) influx. These LTCC-modulating agents regulated IgE+Ag-induced cell activation but not TG-induced cell activation. Inhibition of SOCs by 2-aminoethoxydiphenyl borate reduced both degranulation and production of cytokines, including interleukin-13 and tumor necrosis factor-alpha, whereas LTCC modulation reciprocally regulated degranulation and cytokine production. IgE+Ag, but not TG, induced substantial plasma membrane depolarization, which stimulated a DHP-sensitive Ca(2+) response. Moreover, IgE+Ag-, but not TG-induced mitochondrial Ca(2+) increase was regulated by LTCC modulators. Finally, gene silencing analyses using small interfering RNA revealed that the alpha(1C) (Ca(V)1.2) LTCC mediated the pharmacological effects of the LTCC-modulating agents. These results demonstrate that mast cells express LTCCs, which becomes activated by membrane depolarization to regulate cytosolic and mitochondrial Ca(2+), thereby controlling mast cell activation in a distinct manner from SOCs.
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PMID:L-type Ca2+ channels in mast cells: activation by membrane depolarization and distinct roles in regulating mediator release from store-operated Ca2+ channels. 1912 33

In non-excitable cells, store-operated Ca(2+) channels (SOCs) are the principal routes of Ca(2+) entry. Recently, store-independent Ca(2+) channels which are pharmacologically and/or immunologically similar to L-type Ca(2+) channels (LTCCs) have been shown to exist in various hematopoietic cells, including T cells, B cells and neutrophils. We previously reported that mast cells express LTCCs which regulate mast cell effector responses in a distinct manner from SOCs. In the present study, we examined the possible role for LTCCs in mast cell survival. Both RBL-2H3 mast cells and bone marrow-derived mast cells underwent considerable apoptosis after treatment with thapsigargin (Tg) but not stimulation through the high-affinity IgE receptor (Fc epsilon RI). The LTCC-selective antagonists such as nifedipine greatly augmented Fc epsilon RI-mediated apoptosis, while the LTCC-selective agonist (S)-BayK8644 blocked Tg-induced apoptosis. The modulation of apoptosis was accompanied by altered mitochondrial integrity, as measured with the mitochondrial membrane potential, cytochrome c release and caspase-3/7 activation. Fc epsilon RI stimulation induced mitochondrial Ca(2+) ([Ca(2+)](m)) entry through both SOCs and LTCCs, while Tg evoked [Ca(2+)](m) entry through LTCCs but not SOCs. The LTCC-selective antagonists blocked [Ca(2+)](m) entry, whereas (S)-BayK8644 augmented Tg-induced [Ca(2+)](m) entry. Moreover, blockade of the expression of the alpha(1C) subunit of Ca(v)1.2 LTCC using small-interfering RNA strongly augmented Fc epsilon RI-mediated apoptosis, mitochondrial integrity, and mitochondrial Ca(2+) collapse, and abolished the protective effects of (S)-BayK8644 against Tg-induced apoptosis. These findings suggest that Ca(v)1.2 LTCC protects mast cells against activation-induced cell death by preventing mitochondrial integrity disruption.
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PMID:Ca v 1.2 L-type Ca2+ channel protects mast cells against activation-induced cell death by preventing mitochondrial integrity disruption. 1944 92