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Phosphatidylinositol 4,5‐bisphosphate regulates inspiratory burst activity in the neonatal mouse preBötzinger complex
Author(s) -
Crowder Erin A.,
Saha Margaret S.,
Pace Ryland W.,
Zhang Honglu,
Prestwich Glenn D.,
Del Negro Christopher A.
Publication year - 2007
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2007.134577
Subject(s) - transient receptor potential channel , inositol trisphosphate , chemistry , phosphatidylinositol 4,5 bisphosphate , excitatory postsynaptic potential , intracellular , receptor , neuroscience , biophysics , phosphatidylinositol , inositol , microbiology and biotechnology , biology , biochemistry , signal transduction
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 Ca 2+ ‐activated non‐specific 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 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 Ca 2+ may similarly influence I CAN and thus regulate inspiratory drive potentials, we manipulated intracellular phosphatidylinositol 4,5‐bisphosphate (PIP 2 ) 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 PIP 2 augmented the inspiratory drive potential and diminution of PIP 2 reduced it; sensitivity to flufenamic acid (FFA) suggested that these effects of PIP 2 were I CAN mediated. Inositol 1,4,5‐trisphosphate (IP 3 ), the product of PIP 2 hydrolysis, ordinarily causes IP 3 receptor‐mediated I CAN activation. Simultaneously increasing PIP 2 while blocking IP 3 receptors intracellularly counteracted the reduction in the inspiratory drive potential that normally resulted from IP 3 receptor blockade. We propose that PIP 2 protects I CAN from rundown by interacting directly with underlying ion channels and preventing desensitization, which may enhance the robustness of respiratory rhythm.