A TREK-1 potassium channel blocker with rapid-onset antidepressant and neuroprotective effects.
PE-22-28 is a synthetic analogue of spadin — a peptide derived from the propeptide of sortilin. It blocks TREK-1, a two-pore-domain potassium channel (K2P) that is constitutively expressed in mood-regulating limbic neurons. TREK-1 blockade increases neuronal excitability and serotonin availability, producing rapid antidepressant effects in animal models.
TREK-1 was identified as a key regulator of depressive behaviour after TREK-1 knockout mice showed antidepressant phenotypes. Spadin and its analogue PE-22-28 provided a way to achieve similar TREK-1 blockade pharmacologically.
PE-22-28 shows antidepressant activity within hours in animal models — faster than conventional antidepressants — making it relevant to rapid-onset antidepressant research alongside ketamine-class compounds.