Functional Interaction Between NMDA Receptors and SK Channels in Hypothalamic Magnocellular Neurons: Role in Heart Failure

Neurohumoral activation, which includes elevated plasma levels of vasopressin, is a hallmark of heart failure (HF). However, the precise mechanisms that regulate hypothalamic magnocellular neurosecretory cells (MNCs) neuronal excitability during HF remains incompletely understood. Here, we evaluated whether an increase in intracellular Ca 2+ induced by NMDA receptor activation would evoke a compensatory feedback inhibitory mechanism via activation of Ca 2+ ‐dependent K + channels, and whether this mechanism would contribute to the regulation of MNCs excitability in HF rats. Whole‐cell patch clamp recordings obtained from MNCs (holding potential: −50 mV) in slices from Sham and HF rats showed that focal application of NMDA (50 mM, 300 ms) evoked an inward NMDAR‐mediated current (I NMDAR ) whose magnitude was similar in Sham and HF rats (amplitude: Sham 0.16±0.02 vs HF 0.20±0.02 nA, p>0.05; area: Sham 94±24 vs HF 77±15 nA.ms, p>0.05). I NMDAR was immediately followed by an outward current, whose magnitude was larger in MNCs from HF than Sham rats (amplitude: Sham 0.9±0.1 vs HF 1.6±0.3 nA, p<0.05; area: Sham 215±19 vs HF 410±76 nA.ms, p<0.01). Blockade of K + currents with Cs + revealed that the I NMDAR was in fact significantly larger in MNCs from HF than Sham rats (amplitude: Sham 0.18±0.04 vs HF 0.86±0.02 nA, p<0.05; area: Sham 111±24 vs HF 263±54 nA.ms, p<0.05). Intracellular dialysis of MNCs with the Ca 2+ chelator BAPTA significantly reduced the outward current triggered by NMDAR activation in both groups to the same extent (amplitude: Sham 0.17±0.05 vs HF 0.22±0.07 nA, p>0.05; area: Sham 18±9 vs HF 42±19 nA.ms, p>0.05). Bath application of the SK channel blocker apamin significantly decreased the outward current triggered by I NMDAR in MNCs from HF rats (p<0.05), but this effect was minimal in Sham rats (p>0.05). Finally, current clamp recording showed that focal application of NMDA after SK channel blockade increased the number of evoked spikes both in Sham and HF rats compared to control conditions (Sham 168±25%, p<0.001 vs control; HF 311±71%, p<0.01 vs control), but this effect was exacerbated in HF rats (p=0.06 vs Sham). Taken together, our data supports the presence of a functional coupling between excitatory NMDAR and inhibitory SK channels in MNCs. This interaction is enhanced in HF rats contributing to dampening the NMDAR‐mediated hyperexcitability observed in MNCs during this condition. Support or Funding Information R01HL090948 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .