Mechanisms for L-channel-mediated increase in [Ca(2+)]i and its reduction by anti-bipolar drugs in cultured astrocytes combined with its mRNA expression in freshly isolated cells support the importance of astrocytic L-channels.
The importance of Ca(2+) signaling in astrocytes is undisputed but a potential role of Ca(2+) influx via L-channels in the brain in vivo is disputed, although expression of these channels in cultured astrocytes is recognized. This study shows that an increase in free cytosolic Ca(2+) concentration ([Ca(2+)]i) in astrocytes in primary cultures in response to an increased extracellular K(+) concentration (45mM) is inhibited not only by nifedipine (confirming previous observations) but also to a very large extent by ryanodine, inhibiting ryanodine receptor-mediated release of Ca(2+), known to occur in response to an elevation in [Ca(2+)]i. This means that the actual influx of Ca(2+) is modest, which may contribute to the difficulty in demonstrating L-channel-mediated Ca(2+) currents in astrocytes in intact brain tissue. Chronic treatment with any of the 3 conventional anti-bipolar drugs lithium, carbamazepine or valproic acid similarly causes a pronounced inhibition of K(+)-mediated increase in [Ca(2+)]i. This is shown to be due to an inhibition of capacitative Ca(2+) influx, reflected by decreased mRNA and protein expression of the 'transient receptor potential channel' (TRPC1), a constituent of store-operated channels (SOCEs). Literature data are cited (i) showing that depolarization-mediated Ca(2+) influx in response to an elevated extracellular K(+) concentration is important for generation of Ca(2+) oscillations and for the stimulatory effect of elevated K(+) concentrations in intact, non-cultured brain tissue, and (ii) that Ca(2+) channel activity is dependent upon availability of metabolic substrates, including glycogen. Finally, expression of mRNA for Cav1.3 is demonstrated in freshly separated astrocytes from normal brain.
Department of Clinical Pharmacology and Institute of Pathology and Pathophysiology, China Medical University, Shenyang, PR China.
Enzhi
E
Yan
Baoman
B
Li
Li
L
Gu
Leif
L
Hertz
Liang
L
Peng
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000166:cytology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002220:Carbamazepine / Q000494:pharmacology; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D007477:Ions / Q000737:chemistry; D008094:Lithium / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009543:Nifedipine / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D002492:Central Nervous System Depressants; D007477:Ions; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D012433:Ryanodine; D002220:Carbamazepine; D014635:Valproic Acid; D008094:Lithium; D009543:Nifedipine; D011188:Potassium; D002118:Calcium
Antibipolar drugs; Calcium L-channel; Capacitative calcium uptake; Ryanodine receptor; TRPC1