TY - JOUR

T1 - Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity

AU - Rem, Pascal Dominic

AU - Sereikaite, Vita

AU - Fernandez-Fernandez, Diego

AU - Reinartz, Sebastian

AU - Ulrich, Daniel

AU - Fritzius, Thorsten

AU - Trovò, Luca

AU - Roux, Salome

AU - Chen, Ziyang

AU - Rondard, Philippe

AU - Pin, Jean Philippe

AU - Schwenk, Jochen

AU - Fakler, Bernd

AU - Gassmann, Martin

AU - Barkat, Tania R.

AU - Strømgaard, Kristian

AU - Bettler, Bernhard

N1 - Funding Information: ?B .B.) and the Brain & Behavior Research Foundation (NARSAD Young Investigator Grant Funding Information: This work was supported by The Swiss National Science Foundation (31003A-152970 to B.B.) and the Brain & Behavior Research Foundation (NARSAD Young Investigator Grant 30389 to S.R.). We thank M. Hasegawa and S. Kandler for helpful comments regarding calcium imaging technology. Funding Information: work was supported by The Swiss National Science Foundation (31003A-152970 to

PY - 2023

Y1 - 2023

N2 - Amyloid-β precursor protein (APP) regulates neuronal activity through the release of secreted APP (sAPP) acting at cell-surface receptors. APP and sAPP were reported to bind to the extracellular sushi domain 1 (SD1) of GABAB receptors (GBRs). A 17 amino-acid peptide (APP17) derived from APP was sufficient for SD1 binding and shown to mimic the inhibitory effect of sAPP on neurotransmitter release and neuronal activity. The functional effects of APP17 and sAPP were similar to those of the GBR agonist baclofen and blocked by a GBR antagonist. These experiments led to the proposal that sAPP activates GBRs to exert its neuronal effects. However, whether APP17 and sAPP influence classical GBR signaling pathways in heterologous cells was not analyzed. Here, we confirm that APP17 binds to GBRs with nanomolar affinity. However, biochemical and electrophysiological experiments indicate that APP17 does not influence GBR activity in heterologous cells. Moreover, APP17 did not regulate synaptic GBR localization, GBR-activated K+ currents, neurotransmitter release or neuronal activity in vitro or in vivo. Our results show that APP17 is not a functional GBR ligand and indicate that sAPP exerts its neuronal effects through receptors other than GBRs.

AB - Amyloid-β precursor protein (APP) regulates neuronal activity through the release of secreted APP (sAPP) acting at cell-surface receptors. APP and sAPP were reported to bind to the extracellular sushi domain 1 (SD1) of GABAB receptors (GBRs). A 17 amino-acid peptide (APP17) derived from APP was sufficient for SD1 binding and shown to mimic the inhibitory effect of sAPP on neurotransmitter release and neuronal activity. The functional effects of APP17 and sAPP were similar to those of the GBR agonist baclofen and blocked by a GBR antagonist. These experiments led to the proposal that sAPP activates GBRs to exert its neuronal effects. However, whether APP17 and sAPP influence classical GBR signaling pathways in heterologous cells was not analyzed. Here, we confirm that APP17 binds to GBRs with nanomolar affinity. However, biochemical and electrophysiological experiments indicate that APP17 does not influence GBR activity in heterologous cells. Moreover, APP17 did not regulate synaptic GBR localization, GBR-activated K+ currents, neurotransmitter release or neuronal activity in vitro or in vivo. Our results show that APP17 is not a functional GBR ligand and indicate that sAPP exerts its neuronal effects through receptors other than GBRs.

U2 - 10.7554/eLife.82082

DO - 10.7554/eLife.82082

M3 - Journal article

C2 - 36688536

AN - SCOPUS:85147144590

VL - 12

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e82082

ER -