Functional importance and caffeine sensitivity of ryanodine receptors in primary lymphocytes.
Calcium signaling patterns are important for the specific regulation of activation and effector function in lymphocytes. Studies of [Ca2+]i regulation in lymphocytes, including the involvement of ryanodine receptors (RyR) and the importance of caffeine-sensitive pools, have been carried out mainly in lymphocyte cell lines and the presence and functional importance of these pools in primary lymphocytes has not been addressed. Here we show by confocal microscopy that caffeine caused a prompt but transitory increase of [Ca2+]i in primary lymphocytes, an effect that was inhibited by pre-treatment with ryanodine. Furthermore, the increase of [Ca2+]i in CD4+ and CD8+ MLR T lymphocytes stimulated by 5 microg/ml concanavalin A was significantly inhibited by pretreatment with caffeine. In functional studies, caffeine decreased cytotoxicity against myocyte target cells which is probably related to an altered calcium signaling in CD8+ MLR lymphocytes. Caffeine also terminated spontaneous Ca2+ oscillations and induced a rise in [Ca2+]i in CD4- and CD8- MLR lymphocytes probably of B cell origin. These results demonstrate that caffeine alters Ca2+ signaling in primary lymphocytes, and suggest that RyR, probably the skeletal muscle receptor (RyR-1) and brain receptor (RyR-3), are involved in mediating this effect. It is also possible that blocking of inositol-1,4,5-triphosphate (IP3) receptors is involved in the effects of caffeine on lymphocyte activation.
Ritter
M
M
Division of Cardiology, University of Utah Health Science Center, Salt Lake City 84132, USA.
Menon
S
S
Zhao
L
L
Xu
S
S
Shelby
J
J
Barry
W H
WH
D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects*
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D002118:Calcium