Contribution of Na+/Ca2+ exchange to excessive Ca2+ loading in dendrites and somata of CA1 neurons in acute slice

✍ Scribed by Robert M. Dietz; Lech Kiedrowski; C. William Shuttleworth

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 613 KB
• Volume: 17
• Category: Article
• ISSN: 1050-9631
• DOI: 10.1002/hipo.20336

✦ Synopsis

Abstract

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.