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Dual molecular mechanisms mediate ligand-induced membrane Ig desensitization
J C Cambier1, C L Fisher, H Pickles
1Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO.
Journal of Immunology (Baltimore, Md. : 1950)
|July 1, 1990
Summary
B cell receptor desensitization after antigen binding is not primarily mediated by protein kinase C (PKC) or phosphoinositide hydrolysis. Instead, it involves uncoupling of the receptor from G proteins, suggesting a proximal target like the receptor itself.
Area of Science:
- Immunology
- Molecular Cell Biology
- Signal Transduction
Background:
- Ligation of murine B cell membrane IgM or IgD receptors can lead to desensitization of unligated antigen receptors.
- Previous studies suggested a role for protein kinase C (PKC) in this desensitization process.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying ligand-induced B cell receptor desensitization.
- To investigate the roles of protein kinase C (PKC) and phosphoinositide hydrolysis in this process.
- To identify the specific molecular targets involved in B cell receptor desensitization.
Main Methods:
- Stimulation of B cells with immunoglobulin (Ig) binding ligands and PKC activators (DIC8, PMA).
- Assessment of desensitization using PKC inhibitor staurosporine.
- Biochemical studies to measure PKC activation and phosphoinositide hydrolysis.
- Evaluation of B cell responsiveness to G protein-activating agents (ALF4-, mastoparan).
Main Results:
- Both Ig ligands and PKC activators induced B cell desensitization, but ligand-induced desensitization was longer-lasting and insensitive to staurosporine.
- Biochemical analyses indicated insufficient PKC activation by Ig ligation to account for the observed desensitization.
- Phosphoinositide hydrolysis was neither necessary nor sufficient for ligand-induced desensitization.
- Desensitized B cells showed hyperresponsiveness to G protein activators, indicating intact G protein function and downstream signaling.
- Ligand-induced desensitization appears to involve the uncoupling of membrane Ig from G proteins.
Conclusions:
- Ligand-induced B cell receptor desensitization is mediated by a mechanism independent of protein kinase C (PKC) and phosphoinositide hydrolysis.
- The primary mechanism involves the uncoupling of the B cell receptor from proximal signaling molecules, likely G proteins.
- The target of desensitization is proximal to the receptor, potentially the receptor itself or an associated transducer complex.