PE-22-28 is a shortened, chemically stabilized analog of spadin, a peptide first isolated as a proteolytic fragment of the propeptide of sortilin, a sorting receptor also known as NTSR3. Spadin itself was identified through a series of studies examining how sortilin processing generates a peptide capable of inhibiting the two-pore-domain potassium channel TREK-1, and PE-22-28 was subsequently designed by shortening and modifying the parent spadin sequence to improve stability without losing TREK-1 inhibitory activity. Researchers have studied this class of peptide in cell-based channel assays and in rodent behavioral and synaptic-signaling models, using it as a tool to probe what happens when TREK-1 activity is pharmacologically reduced.
| Attribute | Detail |
|---|---|
| Name | PE-22-28, a shortened spadin analog |
| Parent peptide | Spadin, derived from the sortilin (NTSR3) propeptide |
| Molecular target | TREK-1 (KCNK2), a two-pore-domain potassium channel |
| What studies examine | TREK-1 current inhibition in channel assays, synaptogenesis markers, rodent behavioral-test performance |
| Model systems used | Heterologous TREK-1 expression systems, cultured hippocampal neurons, mice and rats |
| Form supplied | Lyophilized powder, research use only |
What is TREK-1 and why is it a research target?
TREK-1 is a two-pore-domain potassium channel encoded by the KCNK2 gene, expressed broadly in the central nervous system, where it contributes to setting neuronal resting membrane potential and excitability. Researchers became interested in TREK-1 as a target after genetic knockout studies in mice reported behavioral changes consistent with reduced susceptibility to certain aversive stimuli, which prompted a search for pharmacological tools that could inhibit the channel without genetic manipulation. Spadin, and later its shortened analog PE-22-28, emerged from that search as peptide-based TREK-1 inhibitors that could be applied directly in cell and animal experiments (Mazella et al., 2010).
Where does spadin come from, and how does PE-22-28 relate to it?
Spadin was identified as a peptide generated during processing of the sortilin propeptide, and follow-up work proposed that sortilin itself contributes to TREK-1 regulation at the cell membrane, with spadin acting as a released fragment that antagonizes that regulation (Mazella et al., 2018). Because native spadin has a relatively short half-life in vivo, researchers screened truncated and modified versions of the sequence to identify shorter analogs that retained TREK-1 inhibitory activity while showing improved metabolic stability in plasma. PE-22-28 was reported as one of the shortened analogs that displayed better TREK-1 inhibition, improved in vivo stability, and comparable activity in behavioral assays relative to full-length spadin, which is why it is the form most often used in subsequent research rather than the original sequence (Djillani et al., 2017).
What have channel and cell-based studies examined?
Electrophysiology studies using heterologous expression systems have measured TREK-1 current directly, reporting that spadin and its shortened analogs inhibit TREK-1-mediated potassium current in a manner distinct from the channel's other known modulators, such as membrane stretch or intracellular pH changes (Moha Ou Maati et al., 2012). Separately, cultured hippocampal neuron studies have examined synaptogenesis markers, reporting that spadin treatment of neuronal cultures was associated with changes in synapse number and dendritic spine density, effects the authors linked to reduced TREK-1 activity at the neuronal membrane (Devader et al., 2015).
What have rodent studies examined?
Several rodent studies have examined spadin and PE-22-28 in behavioral-test paradigms alongside molecular readouts in brain tissue.
- Moha Ou Maati and colleagues examined spadin in mouse behavioral-test paradigms alongside TREK-1 knockout mice, reporting that spadin's effects on behavioral-test outcomes were absent in TREK-1 knockout animals, supporting TREK-1 as the relevant molecular target rather than an off-target effect (Moha Ou Maati et al., 2012).
- A later study examined interactions between spadin and prefrontal cortex serotonin 5-HT4 and metabotropic glutamate receptor 2 signaling in rats, reporting that spadin's behavioral-test effects depended in part on intact serotonergic signaling in that brain region (Moha ou Maati et al., 2016).
- Djillani and colleagues compared PE-22-28 directly against full-length spadin in mouse behavioral-test assays, reporting comparable activity between the shortened analog and the parent peptide alongside improved plasma stability for the shortened form (Djillani et al., 2017).
These are laboratory models using cell systems and research animals, not clinical studies in humans, and none of the compounds involved were administered as part of a prescribed human or veterinary treatment protocol.
Why does PE-22-28 matter for potassium-channel pharmacology research?
Two-pore-domain potassium channels like TREK-1 are structurally distinct from the voltage-gated potassium channel families that most classical pharmacological tools target, which historically left researchers with few selective inhibitors for this channel class. PE-22-28's value as a research reagent comes from its reported selectivity for TREK-1 in the assays used to characterize it, combined with the practical stability advantage of a shortened peptide sequence over the full-length spadin molecule. Researchers working on peptide molecular weight and sequence questions when comparing analogs like this to their parent peptides may find the walkthrough in how to calculate a peptide's molecular weight and formula from its sequence useful for bench-side verification.
How does PE-22-28 compare to other short neuroscience research peptides?
PE-22-28's TREK-1 mechanism is distinct from the receptor systems engaged by other short peptides studied in neuroscience research, such as the heptapeptides compared in Selank vs Semax or the angiotensin IV-derived compound described in what is Dihexa. Researchers comparing across these categories generally treat channel target, parent molecule and delivery stability as the key variables that distinguish one short neuroscience research peptide from another, rather than assuming similar downstream behavioral readouts imply a shared mechanism.
Handling notes
PE-22-28 is supplied as a lyophilized powder for research use. Like other short peptides, it should be stored per the certificate of analysis and reconstituted using standard bench technique and concentration math; this is bench math for preparing a solution for an assay, not guidance for use in any subject. As with any research peptide, confirm identity and purity from the lot-specific certificate of analysis before use. Lot-specific specs for research-grade PE-22-28 are posted on our PE-22-28 lot page.
Frequently asked questions
Is PE-22-28 the same molecule as spadin?
No. PE-22-28 is a shortened, modified analog of the full-length spadin sequence, designed to retain TREK-1 inhibitory activity while showing improved in vivo stability compared with native spadin.
What receptor or channel does PE-22-28 target?
Published studies describe PE-22-28 and its parent peptide spadin as inhibitors of TREK-1, a two-pore-domain potassium channel encoded by the KCNK2 gene.
Where does spadin come from biologically?
Spadin was identified as a peptide generated during processing of the propeptide of sortilin, a sorting receptor also known as NTSR3, which has been proposed to regulate TREK-1 at the cell membrane.
What model systems have been used to study this peptide?
Published research includes heterologous TREK-1 channel expression systems, cultured hippocampal neurons, and behavioral-test paradigms in mice and rats, including comparisons against TREK-1 knockout animals.
Has PE-22-28 been studied in humans?
The published literature on PE-22-28 and spadin consists of channel assays, cell culture and rodent studies. This article summarizes laboratory research models, not clinical evidence.
How is PE-22-28 supplied for laboratory use?
As a lyophilized powder intended for research use only, sold by lot with an accompanying certificate of analysis.
References
- Mazella J, Pétrault O, Lucas G, et al. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol. 2010;8(4):e1000355. PubMed 20405001.
- Moha Ou Maati H, Veyssiere J, Labbal F, et al. Spadin as a new antidepressant: absence of TREK-1-related side effects. Neuropharmacology. 2012;62(1):278-88. PubMed 21807005.
- Devader C, Khayachi A, Veyssière J, et al. In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin. Br J Pharmacol. 2015;172(10):2604-17. PubMed 25598009.
- Moha ou Maati H, Bourcier-Lucas C, Veyssiere J, et al. The peptidic antidepressant spadin interacts with prefrontal 5-HT4 and mGluR2 receptors in the control of serotonergic function. Brain Struct Funct. 2016;221(1):21-37. PubMed 25233810.
- Mazella J, Borsotto M, Heurteaux C. The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1. Front Pharmacol. 2018;9:1541. PubMed 30670975.
- Djillani A, Pietri M, Moreno S, et al. Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity. Front Pharmacol. 2017;8:643. PubMed 28955242.
Research use only. Homegrown Peptides products are for laboratory research and are not for human or animal use. Nothing in this article is medical advice.
