Ligand-induced desensitization of B-cell membrane immunoglobulin-mediated Ca2+ mobilization and protein kinase C translocation.

Abstract

Binding of ligand to B-cell membrane immunoglobulin (mIlg) can lead to activation of a number of distinct biologic responses, including altered expression of genes encoding c-fos, c-myc, and la, as well as proliferation and immunologic tolerance. Tolerance could reflect a functional uncoupling of receptors from systems that generate intracellular second messengers (i.e., receptor desensitization). To better understand the molecular basis of immune regulation, we examined the ability of mlg to function as a signal transducer after the cell's initial contact with mIg-binding ligand. The results show that ligand binding to as little as 2-10% of mIgM or mIgD renders the cell unresponsive to ligand binding to the reciprocal isotype as judged by Ca2" mobilization and protein kinase C translocation responses. This heterologous receptor desensitization lasts longer than 24 hr and does not reflect loss of receptor from the cell surface. Studies with the calcium ionophore ionomycin, 1,2-dioctanoyl-snglycerol, and the protein kinase inhibitor staurosporine indicate that both protein kinase C-dependent and protein kinase C-independent (staurosporine-insensitive) mechanisms mediate heterologous desensitization after mIg crosslinking.

Tyrosine phosphorylation of components of the B-cell antigen receptors following receptor crosslinking.

“…Cambier et al (28) reported that crosslinking mIgM inhibits subsequent calcium increases in response to mIgD crosslinking and vice versa. They propose that this phenomenon represents heterologous receptor desensitization and is mediated by phosphorylation of all mIg molecules following signaling by either mIgM or mIgD.…”

Rac-mediated Stimulation of Phospholipase Cγ2 Amplifies B Cell Receptor-induced Calcium Signaling

“…They can become less sensitive to this course of action if the Rac-PLC␥ 2 interaction is intact. Both homologous and heterologous desensitization of B cell membrane-immunoglobulin-mediated Ca 2ϩ mobilization have long been known to occur within minutes of anti-immunoglobulin exposure (62). Interestingly, anti-IgM-treated B cells are hyperresponsive to AlF 4 Ϫ and mastoparan (63).…”

Single cell observation of ligand‐induced desensitization of B‐cell membrane immunoglobulin‐mediated calcium signals

“…On the other hand, this was not true for the desensitization of the calcium signals mediated by IgM receptors. [Ca'*]i in 24 h PMA-pretreated BAL17 cells never increased with the addition of the second reciprocal antibody (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)ugl ml), although [Ca'+]i increased with the first antibody stimulation (anti-IgM, 8 pg/ml) (see Fig. 2b).…”

“…'rj, [4][5][6][7][8][9][10][11][12][13][14][15][16]u@ml). These results indicated that B cells (BAL17 cells), once activated by anti-IgM or antiIgD, could no longer be re-activated with the reciprocal isotype antibody binding, which is consistent with the previous findings [9,10]. Then, we confirmed, using a flow cytometer, that the heterologous receptor desensitization did not reflect loss of the receptor from the cell surface (data not shown).…”

“…The mIg-mediated desensitization of calcium signals has been previously observed in B cell populations or sub-populations [9,10]. Here, we have applied a digital imaging fluorescence microscope to observe the desensitization of the calcium signals in individual B cells.…”