FIGURE 4 | Schematic diagram of the phospholipase C-coupled pathway that links M1 muscarinic acetylcholine receptors to Kv7 channels.

The so-called 'mysterious' signal that mediates muscarinic receptor (M1) modulation of Kv7/M channel activity involves the pertussis-toxin-insensitive heterotrimeric G-protein, and specifically the G_q/11 subunit, and phospholipase-C (PLC). Modulation of Kv7 channels seems to involve an unidentified diffusible second messenger that inhibits Kv7 channel activity, either directly or indirectly (via additional downstream molecules). The breakdown products of phosphatidylinositol-(4,5)-bisphosphate (PtdIns(4,5)P₂)— such as diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (Ins(1,4,5)P₃) — and subsequent downstream signals have been excluded as major participants in the slow muscarinic inhibitory pathway. Recent research suggests that membrane PtdIns(4,5)P₂ is a crucial determinant of modulation and might act as a major signalling molecule in this pathway. Ca²⁺ and protein kinase C (PKC) may serve to modify the interaction of the channels with PtdIns(4,5)P₂. ACh, acetylcholine.

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