PE-22-28

PE-22-28 is a synthetic heptapeptide fragment derived from the C-terminal region of spadin — a peptide derived from sortilin, a member of the VPS10 domain receptor family. PE-22-28 specifically targets TREK-1 (TWIK-related potassium channel 1, also known as KCNK2), a two-pore domain background potassium channel that plays a critical role in neuronal excitability, mood regulation, and antidepressant signalling.

TREK-1 is a mechano-sensitive, thermosensitive background K+ channel expressed at high levels in the brain, particularly in limbic structures (hippocampus, amygdala, prefrontal cortex) and spinal cord. TREK-1 maintains the resting membrane potential and regulates neuronal excitability. Published knockout studies have established that TREK-1 deficient mice show antidepressant-like behaviour in multiple paradigms (forced swim test, tail suspension, sucrose preference), positioning TREK-1 blockade as a potential antidepressant mechanism.

PE-22-28 acts as a TREK-1 channel blocker — reducing the background K+ conductance through TREK-1, increasing neuronal excitability and promoting serotonergic neurotransmission. Published research by Djillani et al. (Molecular Pharmacology, 2017) characterised PE-22-28's TREK-1 blocking activity using electrophysiology in TREK-1-expressing HEK293 cells and Xenopus oocytes, and demonstrated antidepressant-like effects in mouse models.

The mechanism connecting TREK-1 blockade to antidepressant effects involves serotonergic signalling: TREK-1 is expressed on serotonergic neurons where its activity controls the neuronal firing rate and serotonin release. TREK-1 blockade increases serotonergic neuron excitability and 5-HT release in limbic projection areas, mimicking the downstream effects of SSRIs through a mechanistically distinct ion channel target.

Research applications: TREK-1 electrophysiology (whole-cell patch clamp in TREK-1-HEK293 cells; two-electrode voltage clamp in Xenopus oocytes); serotonin release assays in raphe neuron cultures; c-Fos immunostaining as a neuronal activation marker; comparison with established TREK-1 blockers (fluoxetine has TREK-1 blocking activity as a secondary mechanism).

MW: approximately 830 Da. Reconstitute in bacteriostatic water at 1mg/mL. Store lyophilised at -20°C. For laboratory and analytical research purposes only.

PE-22-28 electrophysiology research protocol: for TREK-1 channel block characterisation, use HEK293 cells stably expressing human TREK-1 (KCNK2). Whole-cell patch clamp in voltage clamp mode at -80mV holding potential. Apply voltage ramps from -100mV to +60mV (500ms duration) to generate current-voltage relationships. Measure outward TREK-1 current amplitude at 0mV and +40mV in the presence of increasing PE-22-28 concentrations (1nM-10µM) versus vehicle control. Construct concentration-inhibition curves and calculate IC50. Confirm TREK-1 specificity by testing PE-22-28 at the IC50 concentration against TASK-1 (KCNK3), TASK-3 (KCNK9), and TRAAK (KCNK4) in parallel recordings — selectivity among two-pore domain K+ channels is a critical characterisation endpoint.

For serotonergic research downstream of TREK-1 block: use primary mouse raphe neuron cultures (B6 dorsal raphe neurons, DIV14-21) or the RN46A serotonergic cell line. Measure: spontaneous action potential frequency by cell-attached patch clamp before and after PE-22-28 application; serotonin release into conditioned medium by HPLC-ECD or serotonin ELISA following 30-minute PE-22-28 treatment; and c-Fos immunostaining as a neuronal activation marker at 2 hours. Fluoxetine (which has TREK-1 blocking activity) serves as a mechanistic positive control for comparison, allowing direct characterisation of PE-22-28 potency relative to a clinically established compound with the same ion channel target. MW: approximately 830 Da. Store lyophilised at -20°C. For laboratory and analytical research purposes only.