M3 Muscarinic Receptor Interaction with Phospholipase C β3 Determines Its Signaling Efficiency

Abstract

Background: Scaffolding of signaling proteins to GPCRs may increase signaling efficiency and spatial fidelity. Results: Phospholipase C (PLC) ␤3 binding directly to M3 muscarinic receptor intracellular loops involves a non-canonical PDZ interaction. Conclusion: M3 muscarinic receptor binding to PLC␤3 optimizes interactions with substrate and G protein activator. Significance: Scaffolding of PLC enzymes to GPCRs may be important for spatial signal specificity and efficacy.

Preassembled GPCR signaling complexes mediate distinct cellular responses to ultralow ligand concentrations

“…All proteins within the preassembled M 3 R complex interacted with the ICL3 domain of M 3 R. This is also consistent with previous reports of interactions between the M 3 R ICL3 and proteins such as Ga q/11 , Gbg, phospholipase Cb, GRKs, b-arrestins, and casein kinase 2(64)(65)(66)(67). Moreover, conformational changes within this loop region are important for the formation of M 3 R dimers(68).…”

Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness

“…21 Interestingly, a direct interaction between muscarinic receptor and PLCb leading to a close spatial proximity to both its substrate, PIP2, and its activator, Gaq, has been recently described in CHO cells. 22 This observation thus suggests that muscarinic receptor stimulation induces Rac1 activation and its translocation at the plasma membrane promoting Rac1/PLCb2 interaction. Our results further show that this protein interaction is necessary to potentiate IP 3 production, and consequently intracellular Ca 21 rise and contraction in murine and human aSMCs.…”

Gβ 4 γ 1 as a modulator of M3 muscarinic receptor signalling and novel roles of Gβ 1 subunits in the modulation of cellular signalling

“…M3-mAChRs have previously been described to interact directly with PLCβ3 [43]. Of the four isoforms of PLCβ known to exist, PLCβ1, PLCβ3 and PLCβ4 are expressed in HEK 293 cells [35].…”