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Ion Channel-Coupled Receptors (ICCRs) are artificial proteins comprised of a G protein-coupled receptor and a fused ion channel, engineered to couple channel gating to ligand binding. These novel biological objects have potential use in drug screening and functional characterization, in addition to providing new tools in the synthetic biology repertoire as synthetic K + -selective ligand-gated channels. The ICCR concept was previously validated with fusion proteins between the K +  channel Kir6.2 and muscarinic M 2  or dopaminergic D 2  receptors. Here, we extend the concept to the distinct, longer β 2 -adrenergic receptor which, unlike M 2  and D 2  receptors, displayed barely detectable surface expression in our  Xenopus  oocyte expression system and did not couple to Kir6.2 when unmodified. Here, we show that a Kir6.2-binding protein, the N-terminal transmembrane domain of the sulfonylurea receptor, can greatly increase plasma membrane expression of β 2  constructs. We then demonstrate how engineering of both receptor and channel can produce β 2 -Kir6.2 ICCRs. Specifically, removal of 62–72 residues from the cytoplasmic C-terminus of the receptor was required to enable coupling, suggesting that ligand-dependent conformational changes do not efficiently propagate to the distal C-terminus. Characterization of the β 2  ICCRs demonstrated that full and partial agonists had the same coupling efficacy, that an inverse agonist had no effect and that the stabilizing mutation E122 W reduced agonist-induced coupling efficacy without affecting affinity. Because the ICCRs are expected to report motions of the receptor C-terminus, these results provide novel insights into the conformational dynamics of the β 2  receptor.

β2-Adrenergic Ion-Channel Coupled Receptors as Conformational Motion Detectors