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Received December 14, 2004
Revised January 7, 2005
Accepted after revision March 10, 2005
1 Bogomoletz Institute of Physiology, 4 Bogomoletz Street, Kiev, 01024, Ukraine
2 Department of Physiology, University of Cambridge, CB2 3EG, UK
* To whom correspondence should be addressed. E-mail: smm{at}serv.biph.kiev.ua.
Increases in Ca2+ concentration in the nucleus of neurons modulate gene transcription and may be involved in activity-dependent long-term plasticity, apoptosis, and neurotoxicity. Little is currently known about the regulation of Ca2+ in the nuclei of neurons. Investigation of neuronal nuclei is hampered by cellular heterogeneity of the brain where neurons comprise no more than 10% of the cells. The situation is further complicated by large differences in properties of different neurons. Here we report a method for isolating nuclei from identified central neurons. We employed this technique to study nuclei from rat cerebellar Purkinje and granule neurons. Patch-clamp recording from the nuclear membrane of Purkinje neurons revealed numerous large-conductance channels selective for monovalent cations. The nuclear membrane of Purkinje neurons also contained multiple InsP3-activated ion channels localised exclusively in the inner nuclear membrane with their receptor loci facing the nucleoplasm. In contrast, the nuclear membrane of granule neurons contained only a small number of mainly anion channels. Nuclear InsP3Rs were activated by InsP3 with EC50=0.67 µM and the Hill coefficient of 2.5. Ca2+ exhibited a biphasic effect on the receptors elevating its activity at low concentrations and inhibiting it at micromolar concentrations. InsP3 in saturating concentrations did not prevent the inhibitory effect of Ca2+, but strongly increased InsP3R activity at resting Ca2+ concentrations. These data are the first evidence for the presence of intranuclear sources of Ca2+ in neurons. Ca2+ release from the nuclear envelope may amplify Ca2+ transients penetrating in the nucleus from the cytoplasm or generate Ca2+ transients in the nucleus independently from the cytoplasm.
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