Phosphatidylinositol 4,5‐bisphosphate regulates inspiratory burst activity in the neonatal mouse preBötzinger complex

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Abstract
Neurons of the preBötzinger complex (preBötC) form local excitatory networks and synchronously discharge bursts of action potentials during the inspiratory phase of respiratory network activity. Synaptic input periodically evokes a Ca2+‐activated non‐specific cation current (ICAN) postsynaptically to generate 10–30 mV transient depolarizations, dubbed inspiratory drive potentials, which underlie inspiratory bursts. The molecular identity ofICANand its regulation by intracellular signalling mechanisms during inspiratory drive potential generation remains unknown. Here we show that mRNAs coding for two members of the transient receptor potential (TRP) family of ion channels, namely TRPM4 and TRPM5, are expressed within the preBötC region of neonatal mice. Hypothesizing that the phosphoinositides maintaining TRPM4 and TRPM5 channel sensitivity to Ca2+may similarly influenceICANand thus regulate inspiratory drive potentials, we manipulated intracellular phosphatidylinositol 4,5‐bisphosphate (PIP2) and measured its effect on preBötC neurons in the context of ongoing respiratory‐related rhythms in slice preparations. Consistent with the involvement of TRPM4 and TRPM5, excess PIP2augmented the inspiratory drive potential and diminution of PIP2reduced it; sensitivity to flufenamic acid (FFA) suggested that these effects of PIP2wereICANmediated. Inositol 1,4,5‐trisphosphate (IP3), the product of PIP2hydrolysis, ordinarily causes IP3receptor‐mediatedICANactivation. Simultaneously increasing PIP2while blocking IP3receptors intracellularly counteracted the reduction in the inspiratory drive potential that normally resulted from IP3receptor blockade. We propose that PIP2protectsICANfrom rundown by interacting directly with underlying ion channels and preventing desensitization, which may enhance the robustness of respiratory rhythm.