Paradoxical Ca2+ rises induced by low external Ca2+ in rat hippocampal neurones.
Confocal Ca2+ imaging of rat hippocampal slices shows a paradoxical effect of acute reductions of the [Ca2+]o. Upon slice perfusion with low-Ca2+ media, a prompt intracellular Ca2+ rise selectively occurs in neurones. This response is observed only in slices challenged with agonists of group I metabotropic glutamate or M1 muscarinic receptors. In contrast, the intracellular Ca2+ level of non-stimulated neurones is insensitive to reductions of [Ca2+]o. The phenomenon is observed in 20-25 % of cultured cortical neurones. Evidence is provided demonstrating that: (1) this paradoxical response is not due to a non-specific decrease in divalent cation concentration but it is selectively activated by a reduction in [Ca2+]o, being maximal with [Ca2+]o between 0.25 and 0.5 mM; (2) upon maximal stimulation, 70-90 % of CA1-CA3 pyramidal neurones sense a reduction in [Ca2+]o; a weaker response is observed in neurones from the neocortex, whereas neurones from the dentate gyrus and granule cells from the cerebellum fail to respond; (3) conditions that elicit paradoxical Ca2+ responses cause depolarisation and increase the firing rate of hippocampal neurones; (4) paradoxical Ca2+ rises depend, primarily, on Ca2+ influx through L-type voltage-operated Ca2+ channels and to a lesser extent on release from intracellular Ca2+ stores. Inhibition of phospholipase C or protein kinase C failed to suppress the neuronal response, whereas a selective inhibitor of the Src-family of tyrosine kinases abolishes the paradoxical neuronal Ca2+ rise. A model is presented to explain how this response is elicited by contemporaneous reduction of the [Ca2+]o and metabotropic receptor stimulation; implications for the pathophysiology of the CNS are also discussed.
Burgo
Andrea
A
Department of Biomedical Sciences, University of Padua, Via G. Colombo 3, 35121 Padua, Italy.
Carmignoto
Giorgio
G
Pizzo
Paola
P
Pozzan
Tullio
T
Fasolato
Cristina
C
D000818:Animals; D002118:Calcium / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D004553:Electric Conductivity; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D009994:Osmolar Concentration; D017966:Pyramidal Cells / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D003470:Culture Media; D002118:Calcium