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 nonspecific cation current (I_CAN) postsynaptically to generate 10-30 mV transient depolarizations, dubbed inspiratory drive potentials, which underlie inspiratory bursts. The molecular identity of I_CAN and its regulation by intracellular signaling 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 influence I_CAN and thus regulate inspiratory drive potentials, we manipulated intracellular phosphatidylinositol 4,5-biphosphate (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 PIP₂ augmented the inspiratory drive potential and diminution of PIP₂ reduced it; sensitivity to flufenamic acid (FFA) suggested that these effects of PIP₂ were I_CAN-mediated. Inositol 1,4,5-triphosphate (IP₃), the product of PIP₂ hydrolysis, ordinarily causes IP₃ receptor-mediated I_CAN activation. Simultaneously increasing PIP₂ while blocking IP₃ receptors intracellularly counteracted the reduction in the inspiratory drive potential that normally resulted from IP₃ receptor blockade. We propose that PIP₂ protects I_CAN from rundown by interacting directly with underlying ion channels and preventing desensitization, which may enhance the robustness of respiratory rhythm.