title: Signal transduction via the B cell antigen receptor: involvement of a G protein and regulation of signaling.
abstract: The antigen receptors on B lymphocytes, membrane forms of immunoglobulins, transduce signals regulating B cell growth and differentiation by activating a phosphoinositide-specific phospholipase C. In this report, we describe our recent work aimed at understanding this process in greater detail. We have shown that a GTP-binding component is a necessary cofactor in the stimulation of phospholipase C by mIgM. This component has a number of properties in common with the G protein family of receptor-effector coupling components seen in the adenylate cyclase and other signaling systems. For example, analogues of GTP that cannot be hydrolyzed stimulated mIgM-triggered phosphoinositide breakdown, and an analogue of GDP that cannot be converted to GTP inhibited the reactions. Furthermore, aluminum fluoride, which activates known G proteins, also stimulates phosphoinositide breakdown. The G protein that appears to link mIgM to phospholipase C is not one of the well characterized G proteins involved in the regulation of adenylate cyclase or cGMP phosphodiesterase (GS, Gi, and transducin), as judged by its insensitivity to two bacterial toxins that modify these G proteins, cholera toxin and pertussis toxin. Interestingly, analysis of pertussis toxin sensitivity indicates that there are at least 2 distinct G proteins that couple receptors to phospholipase C. For example, the G protein required for chemotactic peptide receptor signaling in neutrophils is sensitive to pertussis toxin, in contrast to the phosphoinositide signaling G protein in B cells. We have also begun to explore the mechanisms by which mIgM signal transduction can be modulated. Stimulation of protein kinase C with phorbol esters or synthetic DG was found to inhibit mIgM-triggered phosphoinositide breakdown. This regulation probably represents a feedback inhibition that would occur with DG produced by phosphoinositide breakdown. Alternatively, there appear to be other signaling pathways that generate DG33, and they could possibly inhibit phosphoinositide breakdown via protein kinase C. This could be an important locus of regulation during B cell activation. For example, other signals could increase or decrease the potency of this feedback inhibition, and thereby adjust the sensitivity of the B cell to antigen. Alternatively, other agents could stimulate protein kinase C directly, or could stimulate another protein kinase which can do the same thing in this regard, and thereby make the B cell insensitive to antigen by preventing antigen receptor signaling.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Microbiology, University of California, San Francisco 94143-0552.
authors.forename: A L
authors.initials: AL
authors.lastname: DeFranco
authors.forename: M R
authors.initials: MR
authors.lastname: Gold
mesh_terms: D037361:Adenylate Cyclase Toxin; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D002772:Cholera Toxin / Q000494:pharmacology; D004789:Enzyme Activation; D005246:Feedback; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives; D007075:Immunoglobulin M / Q000378:metabolism*; D007295:Inositol Phosphates / Q000378:metabolism; D037342:Pertussis Toxin; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D010716:Phosphatidylinositols / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D000954:Antigens, Surface; D007075:Immunoglobulin M; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D011947:Receptors, Antigen, B-Cell; D010566:Virulence Factors, Bordetella; D006160:Guanosine Triphosphate; D002772:Cholera Toxin; D037342:Pertussis Toxin; D011493:Protein Kinase C; D010727:Phosphoric Diester Hydrolases; D019204:GTP-Binding Proteins; D043265:Phosphatidylinositol Diacylglycerol-Lyase