Keyong Publication in Cell Reports

 

In a recent paper, Keyong uncovered a large subthreshold membrane potential oscillation in the CO₂/H⁺-sensitive retrotrapezoid nucleus (RTN) neurons that drive brainstem breathing circuits (Cell Reports 34: 108714, 2021). As reported for the few other neuron types where similar phenomena have been observed, these oscillations required increased intracellular Ca²⁺ levels provided by L-type Ca channels. However, Keyong also found that that the oscillations were inhibited by blockers of TRPM4, a calcium-dependent cation channel expressed in RTN neurons. The TRPM4 blockers also interfered with excitatory neuromodulation of RTN neurons. Moreover, our UVA Pharmacology colleague, Stephen Abbott, showed that microinjection of TRPM4 blockers directly into the mouse RTN inhibited respiratory output in vivo. This work therefore identifies a novel electrophysiological role for the versatile TRPM4 channel in mediating subthreshold oscillations and driving spontaneous and stimulated neuronal activity. We believe the large TRPM4-dependent oscillations support the pacemaker-like activity in RTN neurons that is required to maintain regular breathing, especially during sleep.