Isoform-specific regulation of immune cell reactivity by the catalytic subunit of protein kinase A (PKA).
There are two major genes encoding the catalytic subunits of protein kinase A, Calpha and Cbeta. The functional significance of these isoforms is enigmatic. Lymphoid cells of the immune system express both Calpha and Cbeta. In this study we tested the role of Calpha and Cbeta in regulating immune cell reactivity to antigens using mice carrying a targeted disruption of the Calpha and Cbeta gene respectively. Calpha and Cbeta ablation both resulted in a 50% reduction in PKA-specific kinase activity and the level of PKA type I but not PKA type II. Moreover, despite that C subunit ablation did not affect immune cell development and homeostasis, Calpha but not Cbeta ablation augmented expression of the activation marker CD69 on lymphocytes. CD69 induction coincided with immune cell hyperresponsiveness and was associated with reduced sensitivity to cAMP-mediated inhibition of anti-CD3 induced T cell proliferation. Our results imply that Calpha is required for normal immune cell reactivity and demonstrates isoform-specific effects and non-redundant functions of C subunit isoforms expressed in the same cell.
Funderud
Ane
A
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway.
Aas-Hanssen
Kristin
K
Aksaas
Anne Kristin
AK
Hafte
Tilahun T
TT
Corthay
Alexandre
A
Munthe
Ludvig A
LA
Orstavik
Sigurd
S
Skålhegg
Bjørn S
BS
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001402:B-Lymphocytes / Q000201:enzymology*; D017252:CD3 Complex / Q000378:metabolism; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000378:metabolism*; D005434:Flow Cytometry; D007527:Isoenzymes / Q000378:metabolism; D037181:Lectins, C-Type; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology*; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D000242:Cyclic AMP; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D007527:Isoenzymes; D037181:Lectins, C-Type; D000099192:CD69 Antigens; C463959:protein kinase A Calpha