Interactions Between PE-22-28 and Nerve Cells

PE-22-28 is a 7-amino-acid peptide derived from the degradation products of spadin (PE 12-28), which itself originates from the post-translational maturation of sortilin. Researchers have posited that the peptide may act primarily through a TREK-1 blockade, and data collected from in vitro cellular samples suggest it may do so with considerably greater affinity than its parent peptide spadin.

TREK-1 is a two-pore domain potassium channel involved in stabilizing membrane potential and dampening neuronal excitability, possibly linked to better-supported serotonergic neurotransmission. Beyond channel interaction, PE-22-28 may additionally engage neuroplasticity pathways, such as promoting neurogenesis and synaptogenesis.

 

Research

PE-22-28 and Serotonin Synthesis

Studies by Djillani et al. suggest that PE-22-28 may act mainly by blocking TREK-1, a potassium channel that appears to dampen serotonin-related activity when it is too active.⁽¹⁾ Normally, these channels appear to be operated by the so-called sortilin system, which is hypothesized to help activate TREK-1 channels potentially. In contrast, a fragment of that system called the spadin fragment may mitigate it.

PE-22-28 may be described as a shortened, more potent version of spadin, which itself comes from the sortilin system. Thus, the peptide may work by blocking TREK-1, which may help serotonergic neurons fire more easily and support stronger serotonergic signaling. According to research by Okada et al., the peptide may have direct interactions with some types of neurons, such as neurons stemming from the dorsal raphe nucleus.⁽²⁾

Their research suggests that PE-22-28 may mitigate the uptake of TREK-1 in that nerve cell population to reduce the potassium leak current that normally keeps those neurons suppressed. Specifically, they suggest that “the peptide [may] block the channel and thereby activate the serotonergic neurons, resulting in the facilitation of serotonergic transmission.” Importantly, the researchers also note that TREK-1 may be expressed in cardiac cells, which raises a theoretical concern that blockade may not be entirely selective and potentially cause irregular cardiac cell functions.

On the other hand, research by Moha ou Maati et al. suggests that there may also be an indirect pathway in which PE-22-28 may induce a TREK-1 blockade, which first increases the activity of pyramidal neurons.⁽³⁾ Such neurons may then send excitatory glutamatergic input to nerve cells stemming from the dorsal raphe and secondarily support serotonin neuron firing. This is based on their research suggesting the TREK-1 channels may be functionally coupled to mGluR2 receptors, since blocking mGluR2/3 with LY 341495 seemingly occludes spadin’s actions rather than adding to it, pointing to a shared mechanism at the same channel.

PE-22-28 and Neuroplasticity

Later research by Djillani et al. suggests that PE-22-28 may not only support serotonin signaling neurons but may also engage neuroplasticity pathways that may interact with the cells.⁽⁴⁾ The researchers suggested that PE-22-28 may promote neurogenesis after relatively short exposure periods. Specifically, they noted an apparent increase in Postsynaptic Density Protein 95 (PSD-95) expression, which may hint at better-supported synaptogenesis, meaning the formation of new connections between nerve cells.

They posit that PSD-95 may act like a structural organizer that helps synapses mature and stabilize. If PSD-95 levels appear to rise, it may indicate an increase in the number of functional synapses and better-supported recruitment of AMPA receptors, which may carry much of the signal between neurons. Further research by Djillani et al. also points to a possible connection between PE-22-28 and BDNF.⁽⁵⁾ Specifically, BDNF is considered to be another protein involved in nerve cell growth and plasticity.

Researchers have suggested that sortilin may play an important role in directing BDNF into the correct secretory channels within cells. Since PE-22-28 is derived from a peptide that binds sortilin with relatively high affinity, it may potentially alter how sortilin handles BDNF.

The researchers also posited that by inducing a TREK-1 blockade and leading to increased serotonergic activity, PE-22-28 may be directly linked to BDNF expression through the activation of a signaling protein called CREB.

The scientists also commented that they observed “a rapid increase in both mRNA expression and protein level of brain-derived neurotrophic factor (BDNF) in the hippocampus” during evaluation.

According to data collected in laboratory settings, researchers have observed in studies with spadin increased CREB phosphorylation and hippocampal neurogenesis. This increase was at times observed within four days of evaluation in laboratory settings, a timeline that some researchers suggest may be consistent with BDNF-related plasticity processes. The elevated PSD-95 expression observed with PE-22-28 evaluation may also partly reflect synaptic consolidation downstream of such mechanisms.

PE-22-28 and Neuroprotection

Research on spadin by Devader et al. suggests that peptides like PE-22-28 may not block only TREK-1 but also activate downstream signaling pathways associated with neuroprotection, such as ERK1/2 and PI3K/Akt, two intracellular pathways associated with survival and growth.⁽⁶⁾

Specifically, the researchers suggested that the peptide may protect neurons from staurosporine-induced apoptosis during laboratory experimentation via the PI3K/Akt pathway. On the other hand, the ERK pathway may also be activated in association with the peptide’s potential for synaptic plasticity.

Spadin and associated peptides like PE-22-28 may also promote the maturation of dendritic spines, shifting the balance toward larger, more stable mushroom-type spines without changing total spine number. More specifically, the study proposes two sequential phases of action for the peptide, when applied to cell cultures, which may include an early phase involving BDNF upregulation and serotonin release, and a later phase involving spine maturation and synaptic consolidation. Additionally, spadin appears to induce internalization of both TREK-1 and sortilin, possibly contributing to sustained channel inactivation beyond simple blockade.

NOTE: These products are intended for laboratory research use only. This peptide is not intended for personal use. Please review and adhere to our Terms and Conditions before ordering.

 

References:

1. Djillani, A., Mazella, J., Heurteaux, C., & Borsotto, M. (2019). Role of TREK-1 in Health and Disease, Focus on the Central Nervous System. Frontiers in pharmacology, 10, 379. https://doi.org/10.3389/fphar.2019.00379
2. Okada, M., & Ortiz, E. (2022). Viral vector-mediated expressions of venom peptides as novel gene therapy for anxiety and depression. Medical Hypotheses, 166, 110910.
3. Moha ou Maati, H., Bourcier-Lucas, C., Veyssiere, J., Kanzari, A., Heurteaux, C., Borsotto, M., Haddjeri, N., & Lucas, G. (2016). The peptidic antidepressant spadin interacts with prefrontal 5-HT(4) and mGluR(2) receptors in the control of serotonergic function. Brain structure & function, 221(1), 21–37. https://doi.org/10.1007/s00429-014-0890-x
4. Djillani, A., Pietri, M., Moreno, S., Heurteaux, C., Mazella, J., & Borsotto, M. (2017). Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity. Frontiers in pharmacology, 8, 643. https://doi.org/10.3389/fphar.2017.00643
5. Djillani, A., Pietri, M., Mazella, J., Heurteaux, C., & Borsotto, M. (2019). Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin. Pharmacology & therapeutics, 194, 185–198. https://doi.org/10.1016/j.pharmthera.2018.10.003
6. Devader, C., Khayachi, A., Veyssière, J., Moha Ou Maati, H., Roulot, M., Moreno, S., Borsotto, M., Martin, S., Heurteaux, C., & Mazella, J. (2015). In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin. British journal of pharmacology, 172(10), 2604–2617. https://doi.org/10.1111/bph.13083