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J Biol Chem, Vol. 274, Issue 20, 13859-13864, May 14, 1999

Coupling of M₂ Muscarinic Receptors to Membrane Ion Channels via Phosphoinositide 3-Kinase  and Atypical Protein Kinase C

Yong-Xiao Wang, Prasad D. K. Dhulipala, Lei Li, Jeffrey L. Benovic, and Michael I. Kotlikoff

From the Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and the  Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

We report a novel signaling pathway linking M₂ muscarinic receptors to metabotropic ion channels. Stimulation of heterologously expressed M₂ receptors, but not other G_i/G_o-associated receptors (M₄ or _2c), activates a calcium- and voltage-independent chloride current in Xenopus oocytes. We show that the stimulatory pathway linking M₂ receptors to these chloride channels consists of G stimulation of phosphoinositide 3-kinase  (PI-3K), formation of phosphatidylinositol 3,4,5-trisphosphate (PIP₃), and activation of atypical protein kinase C (PKC). The chloride current is activated in the absence of M₂ receptor stimulation by the injection of PIP₃, and PIP₃ current activation is blocked by a pseudosubstrate inhibitory peptide of atypical PKC but not other PKCs. Moreover, the current is activated by injection of recombinant PKC at concentrations as low as 1 nM. M₂ receptor-current coupling was disrupted by inhibiton of PI-3K and by injection of binding peptides, but it was not affected by expression of dominant negative p85 cRNA. We also show that this pathway mediates M₂ receptor coupling to metabotropic nonselective cation channels in mammalian smooth muscle cells, thus demonstrating the broad relevance of this signaling cascade in neurotransmitter signaling.

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