PSEMs

PSAM and PSEM Mechanism of Action

Chemogenetic tools based on G protein-coupled receptors (GPCRs), like DREADDs and DREADD ligands, enable control of neuronal activity by engaging complex intracellular signaling pathways that result in changes in ion flux through endogenously expressed ion channels. PSAMs are chimeric ion channels that provide a more direct route to manipulation of ion flux and neuronal activity.

PSAMs were developed from initial research demonstrating that the ligand binding domain of the α7 nicotinic ACh receptor (nAChR) can be transplanted onto the ion pore domain of other ligand-gated ion channels, including 5-HT₃ receptors and Glycine receptors. This creates a chimeric ion channel that has α7 nAChR ligand binding properties, with the ion permeability properties of the ion pore domain used. To abolish ACh binding, selective mutations were introduced in the α7 nAChR ligand binding domain, resulting in PSAMs that are only bound by inert PSEM ligands. The ligand binding domain may harbor a single or multiple mutation, and PSAMs are named according to their mutations and linked ion pore domain.

To manipulate neuronal signaling, PSAMs must be expressed in cells, either in culture or in vivo, which is most commonly achieved through viral vector expression systems. The effect that PSEM binding has on neuronal signaling depends on the receptor from which the ion pore domain of the PSAM originates. For example, PSEM 308 (Cat. No. 6425) binding to PSAM^L141F,Y115F-5-HT₃ leads to neuronal activation via cation influx, while PSEM 308 binding to PSAM^L141F-GlyR inhibits neuronal activity through anion influx.

Figure 1: Activating PSAMs are composed of a mutated α7 nAChR ligand binding domain spliced with the ion pore domain of a cation selective channel, such as 5-HT₃. Binding of PSEMs to activating PSAMs results in influx of cations and activation of neuronal activity. Inhibitory PSAMs are composed of a mutated α7 nAChR ligand binding domain spliced with the ion pore domain of an anion selective channel, such as GlyR. Binding of PSEMs to inhibitory PSAMs results in influx of anions and inhibition of neuronal activity.

Development of PSAM⁴ Chimeric Ion Channels and Ultrapotent PSEMs

More recently, further research into PSAMs and PSEMs has led to the development of ultrapotent PSEMs, known as uPSEMs. These compounds have been developed from the α4β2 nAChR partial agonist, Varenicline (Cat. No. 3754). A low concentration of varenicline inhibits activity of neurons expressing PSAM^L141F-GlyR. The potency of varenicline was increase by introducing further mutations into the PSAM ligand binding domain, resulting in highly potent (EC₅₀ < 10 nM) activity of varenicline at α7^{L131G,Q139L,Y217F}-5-HT₃ (PSAM⁴-5-HT₃) and PSAM⁴-GlyR chimeric ion channels. Subsequently, compounds were developed that retain the high potency of varenicline at PSAM⁴ but improve selectivity for PSAMs over endogenous targets. uPSEM 817 (Cat. No. 6866) is an ultrapotent (EC₅₀ < 1nM) and highly selective PSAM⁴-5-HT₃ and PSAM⁴-GlyR agonist, which is brain penetrant. This compound enables direct and non-invasive control of neuronal activity, in vivo in mice and non-human primates.

Literature for PSEMs

Tocris offers the following scientific literature for PSEMs to showcase our products. We invite you to request* your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.

Chemogenetics Research Bulletin

Produced by Tocris, the chemogenetics research bulletin provides an introduction to chemogenetic methods to manipulate neuronal activity. It outlines the development of RASSLs, DREADDs and PSAMs, and the use of chemogenetic compounds. DREADD ligands and PSEMs available from Tocris are highlighted.

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