PSEMs

Pharmacologically Selective Effector Molecules (PSEMs) are inert ligands, specific for genetically-modified, chimeric ion channels, termed Pharmacologically Selective Actuator Modules (PSAMs). PSAMs containing the 5-HT3 ion pore domain allow activation of neuronal activity, while GlyR and GABAc containing chimeras are inhibitory

Products
Background
Literature (3)

Agonists

Cat. No. Product Name / Activity
6425 PSEM 308 hydrochloride
PSAML141F-GlyR and PSAML141F,Y115F-5-HT3 chimeric ion channel agonist
6426 PSEM 89S
PSAML141F-GlyR and PSAML141F,Y115F-5-HT3 chimeric ion channel agonist
6865 uPSEM 792 hydrochloride
Highly potent PSAM4-GlyR and PSAM4-5-HT3 chimeric ion channel agonist; brain-penetrant
6866 uPSEM 817 tartrate
Highly potent and selective PSAM4-GlyR and PSAM4-5-HT3 chimeric ion channel agonist; brain-penetrant

Other

Cat. No. Product Name / Activity
2459 Tropisetron hydrochloride
Activates α7Q79G-GlyR; also potent 5-HT3 antagonist and α7 nAChR partial agonist
3754 Varenicline tartrate
Potent activator of PSAM4-5-HT3 and PSAM4-GlyR; also selective α4β2 nAChR partial agonist

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 habor 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 iron pore domain of the PSAM originates. For example, PSEM 308 (Cat. No. 6425) binding to PSAML141F,Y115F-5-HT3 leads to neuronal activation via cation influx, while PSEM 308 binding to PSAML141F-GlyR inhibits neuronal activity through anion influx.

PSEMs Mechanism of Action.

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 PSAML141F-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 α7L131G,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.


GPCR

GPCR Product Listing

A collection of over 450 products for G protein-coupled receptors, the listing includes research tools for the study of:

  • Rhodopsin-like Receptors
  • Glutamate Receptors
  • Frizzled Receptors
  • GPCR Signaling
Ion Channel

Ion Channel Product Listing

A collection of around 500 products for ion channel research, the listing includes research tools for the study of:

  • Ligand-gated ion channels
  • Voltage-gated ion channels
  • Other Ion Channels
Chemogenetics

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.