Differential regulation of surface Ig- and Lyb2-mediated B cell activation by cyclic AMP. I. Evidence for alternative regulation of signaling through two different receptors linked to phosphatidylinositol hydrolysis in murine B cells.
The differential effect of cAMP on the regulation of early biochemical and cellular functions mediated through two different receptors on murine B cells are reported here. Surface IgM, the Ag receptor, and Lyb2, a 45-kDa differentiation Ag are concomitantly expressed on mature murine B lymphocytes. Triggering of B cells through these molecules, independently, resulted in inositol 1,4,5-triphosphate (IP3) generation, increase in intracellular Ca2+ levels, and cell enlargement associated with progression of cells from G0 to G1 ultimately resulting in DNA synthesis. Pretreatment of resting B cells with cholera toxin as well as other agents that raise the intracellular cAMP [(cAMP)i] such as forskolin, N6,2'-O-dibutyryl cyclic AMP, and 3-isobutyl-1 methyl xanthine inhibited the Ag receptor but not Lyb2-mediated DNA synthesis. The elevation of (cAMP)i inhibited the surface IgM but not Lyb2-mediated IP3 generation, Ca2+ response, and progression from G0 to G1 phase of the cell cycle. Failure of forskolin or N6,2'-O-dibutyryl cyclic AMP to inhibit Lyb2-mediated responses did not appear to be due to induction of cAMP-specific phosphodiesterase activity. Concentrations of H8 [N-(2-(methylamino)-ethyl)-5-isoquinoline sulfonamide, diHCl] inhibitory to cAMP dependent PKA prevented the inhibitory effect of forskolin on surface IgM-mediated Ca2+ response, suggesting that cAMP exerted its effects through PKA. These findings suggest that distinct PLC-coupled receptors, such as sIgM and Lyb2 molecules in B cells, may use either alternative mechanisms for phosphatidylinositol 4,5-bisphosphate hydrolysis or may use different intermediary transducer molecules that differ in their sensitivity to increased (cAMP)i levels. Thus "cross-talk" among cAMP and phosphatidylinositol signaling pathways was demonstrated for IgM but not Lyb2-mediated B cell activation.
Muthusamy
N
N
Department of Microbiology and Immunology, University of Kentucky, Lexington 40536.
Baluyut
A R
AR
Subbarao
B
B
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D000950:Antigens, Ly / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D005260:Female; D006868:Hydrolysis; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D010716:Phosphatidylinositols / Q000378:metabolism*; D011494:Protein Kinases / Q000502:physiology; D011946:Receptors, Antigen / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D011990:Receptors, Transferrin / Q000032:analysis; D015398:Signal Transduction
D000950:Antigens, Ly; D010716:Phosphatidylinositols; D011946:Receptors, Antigen; D011947:Receptors, Antigen, B-Cell; D011990:Receptors, Transferrin; D005576:Colforsin; D002772:Cholera Toxin; D000242:Cyclic AMP; D011494:Protein Kinases; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine