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Contribution of Na + /Ca 2+ exchange to excessive Ca 2+ loading in dendrites and somata of CA1 neurons in acute slice
Author(s) -
Dietz Robert M.,
Kiedrowski Lech,
Shuttleworth C. William
Publication year - 2007
Publication title -
hippocampus
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.767
H-Index - 155
eISSN - 1098-1063
pISSN - 1050-9631
DOI - 10.1002/hipo.20336
Subject(s) - chemistry , ouabain , biophysics , intracellular , sodium calcium exchanger , calcium , extracellular , hippocampal formation , calcium in biology , neuroscience , medicine , endocrinology , sodium , biochemistry , biology , organic chemistry
Multiple Ca 2+ entry routes have been implicated in excitotoxic Ca 2+ loading in neurons and reverse‐operation of sodium–calcium exchangers (NCX) has been shown to contribute under conditions where intracellular Na + levels are enhanced. We have investigated effects of KB‐R7943, an inhibitor of reverse‐operation NCX activity, on Ca 2+ elevations in single CA1 neurons in acute hippocampal slices. KB‐R7943 had no significant effect on input resistance, action potential waveform, or action potential frequency adaptation, but reduced L‐type Ca 2+ entry in somata. Nimodipine was therefore included in subsequent experiments to prevent complication from effects of L‐type influx on evaluation of NCX activity. NMDA produced transient primary Ca 2+ increases, followed by propagating secondary Ca 2+ increases that initiated in apical dendrites. KB‐R7943 had no significant effect on primary or secondary Ca 2+ increases generated by NMDA. The Na + /K + ATPase inhibitor ouabain (30 μM) produced degenerative Ca 2+ overload that was initiated in basal dendrites. KB‐R7943 significantly reduced initial Ca 2+ increases and delayed the propagation of degenerative Ca 2+ loads triggered by ouabain, raising the possibility that excessive intracellular Na + loading can trigger reverse‐operation NCX activity. A combination of NMDA and ouabain produced more rapid Ca 2+ overload, that was contributed to by NCX activity. These results suggest that degenerative Ca 2+ signaling can be triggered by NMDA in dendrites, before intracellular Na + levels become sufficient to reverse NCX activity. However, since Na + /K + ATPase inhibition does appear to produce significant reverse‐operation NCX activity, this additional Ca 2+ influx pathway may operate in ATP‐deprived CA1 neurons and play a role in ischemic neurodegeneration. © 2007 Wiley‐Liss, Inc.