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The Journal of Neuroscience, March 30, 2005, 25(13):3400-3413; doi:10.1523/JNEUROSCI.3231-04.2005

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Cellular/Molecular
Relationship between Membrane Phosphatidylinositol-4,5-Bisphosphate and Receptor-Mediated Inhibition of Native Neuronal M Channels

Joanna S. Winks,¹ Simon Hughes,² Alexander K. Filippov,² Lucine Tatulian,² Fe C. Abogadie,² David A. Brown,² and Stephen J. Marsh²

¹Ion Channel Pharmacology Group, IPC 388, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, United Kingdom, and ²Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom

The relationship between receptor-induced membrane phosphatidylinositol-4'5'-bisphosphate (PIP₂) hydrolysis and M-current inhibition was assessed in single-dissociated rat sympathetic neurons by simultaneous or parallel recording of membrane current and membrane-to-cytosol translocation of the fluorescent PIP₂/inositol 1,4,5-trisphosphate (IP₃)-binding peptide green fluorescent protein-tagged pleckstrin homology domain of phospholipase C (GFP-PLC-PH). The muscarinic receptor agonist oxotremorine-M produced parallel time- and concentration-dependent M-current inhibition and GFP-PLC-PH translocation; bradykinin also produced parallel time-dependent inhibition and translocation. Phosphatidylinositol-4-phosphate-5-kinase (PI5-K) overexpression reduced both M-current inhibition and GFP-PLC-PH translocation by both oxotremorine-M and bradykinin. These effects were partly reversed by wortmannin, which inhibits phosphatidylinositol-4-kinase (PI4-K). PI5-K overexpression also reduced the inhibitory action of oxotremorine-M on PIP₂-gated G-protein-gated inward rectifier (Kir3.1/3.2) channels; bradykinin did not inhibit these channels. Overexpression of neuronal calcium sensor-1 protein (NCS-1), which increases PI4-K activity, did not affect responses to oxotremorine-M but reduced both fluorescence translocation and M-current inhibition by bradykinin. Using an intracellular IP₃ membrane fluorescence-displacement assay, initial mean concentrations of membrane [PIP₂] were estimated at 261 µM (95% confidence limit; 192-381 µM), rising to 693 µM (417-1153 µM) in neurons overexpressing PI5-K. Changes in membrane [PIP₂] during application of oxotremorine-M were calculated from fluorescence data. The results, taken in conjunction with previous data for KCNQ2/3 (Kv7.2/Kv7.3) channel gating by PIP₂ (Zhang et al., 2003), accorded with the hypothesis that the inhibitory action of oxotremorine-M on M current resulted from depletion of PIP₂. The effects of bradykinin require additional components of action, which might involve IP₃-induced Ca²⁺ release and consequent M-channel inhibition (as proposed previously) and stimulation of PIP₂ synthesis by Ca²⁺-dependent activation of NCS-1.

Key words: PIP₂; M current; neuronal excitability; G-protein-coupled receptors; PLC; sympathetic neurons

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Received Aug 6, 2004; revised February 11, 2005; accepted February 11, 2005.

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