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Model of receptor-operated TRPC4 and -5 channel activation by DAG. In the DAG-insensitive, inactive channel conformation, PIP2 and NHERF proteins are bound to the C terminus. PIP2 depletions, PKC inhibition, NHERF down-regulation, and coexpression of the NHERF1–E68A mutant lead to DAG sensitivity. PLC-dependent or independent PIP2 depletions cause a conformational change of the C terminus, leading to dissociation of NHERF, which results in DAG sensitivity of TRPC4 and -5 channels.
