Recovery of deficient cholinergic calcium signaling by adenosine in cultured rat cortical astrocytes.
The regulation of the cholinergic calcium signaling in astroglial cells is thought to play a crucial role in the pathogenesis of Alzheimer's disease. We investigated the action of the cell modulator adenosine on acetylcholine (Ach)-mediated intracellular calcium ([Ca(2+)](i)) transients in cultured rat cortical astrocytes using the Ca(2+) imaging technique. The stable adenosine analog 2-chloroadenosine (2ClA) potentiated the [Ca(2+)](i) rise induced by activation of muscarinic Ach receptors by shifting approximately 30-fold the half-effective Ach concentration. This 2ClA effect was maintained upon removal of extracellular Ca(2+), indicating that Ach-induced [Ca(2+)](i) elevation was due mainly to Ca(2+) mobilization from intracellular stores. Pharmacological studies demonstrated that the 2ClA action was mediated by A1 receptors. Incubation with pertussis toxin abrogated the 2ClA effect but left unchanged the [Ca(2+)](i) rise produced by Ach alone. The [Ca(2+)](i) response elicited by Ach alone was abolished upon blockade of muscarinic receptor subtypes that stimulate phospholipase C, whereas the [Ca(2+)](i) elevation generated by the combined action of subthreshold Ach and 2ClA was not affected. Collectively, these results suggest that the impaired cholinergic signaling, the cardinal symptom of Alzheimer's disease, can be reinforced at the second messenger level by an alternative intracellular Ca(2+) mobilizing path, which can be brought into play by the concomitant activation of A1 purinoceptors and muscarinic receptors negatively coupled to adenylyl cyclase.
Ferroni
Stefano
S
Department of Human and General Physiology, University of Bologna, Bologna, Italy. ferroni@biocfarm.unibo.it
Marchini
Cristina
C
Ogata
Tadanori
T
Schubert
Peter
P
D015762:2-Chloroadenosine / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology*; D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism*; D000322:Adrenergic Agonists / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D011976:Receptors, Muscarinic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D011983:Receptors, Purinergic / Q000378:metabolism
D000322:Adrenergic Agonists; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D011983:Receptors, Purinergic; D015762:2-Chloroadenosine; D000241:Adenosine; D000109:Acetylcholine; D002118:Calcium