Abstract
PICK1 (protein interacting with C-kinase 1) is a peripheral membrane protein that interacts with diverse membrane proteins. PICK1 has been shown to regulate the clustering and membrane localization of synaptic receptors such as AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, metabotropic glutamate receptor 7, and ASICs (acid-sensing ion channels). Moreover, recent evidence suggests that PICK1 can mediate the trafficking of various vesicles out from the Golgi complex in several cell systems, including neurons. However, how PICK1 affects vesicle-trafficking dynamics remains unexplored. Here, we show that PICK1 mediates vesicle trafficking by interacting with syntabulin, a kinesin-binding protein that mediates the trafficking of both synaptic vesicles and mitochondria in axons. Syntabulin recruits PICK1 onto microtubule structures and mediates the trafficking of PICK1-containing vesicles along microtubules. In neurons, syntabulin alters PICK1 expression by recruiting PICK1 into axons and regulates the trafficking dynamics of PICK1-containing vesicles. Furthermore, we show that syntabulin forms a complex with PICK1 and ASICs, regulates ASIC protein expression in neurons, and participates in ASIC-induced acidotoxicity.
Highlights
PICK1 is a peripheral membrane protein expressed mainly in the brain, testis, and pancreas[1,2,3]
Syntabulin belongs to a family of proteins that are involved in kinesin and mitochondrion binding and vesicle trafficking[24,25,26], dorsal axis formation and stimulated insulin secretion[27,28,29]
Our results showed that the BAR domain of PICK1 mainly mediates the syntabulin binding and that the syntabulin central syntaxin-binding domain (SBD) is responsible for PICK1 binding (Fig. 1B)
Summary
PICK1 (protein interacting with C-kinase 1) is a peripheral membrane protein expressed mainly in the brain, testis, and pancreas[1,2,3]. In the case of AMPA receptors, PICK1 binds to the GluA2 subunit in a PDZ-dependent manner[1,2], and the BAR domain of PICK1 binds to lipids and targets the proteins to synapses or dendritic shafts by forming distinct dimeric complexes[3,22]. PICK1 serves as a linker for the binding of vesicle cargo proteins and vesicle targeting, the trafficking route through which PICK1 transports the bound receptors remains unknown, as does the underlying trafficking mechanism To address these questions, we performed yeast-two-hybrid screening by using PICK1 as the bait and identified a microtubule trafficking-associated protein, syntabulin/golsyn (hereafter syntabulin), as a previously unrecognized PICK1-interacting partner. We report that syntabulin contributes to PICK1-mediated surface expression of ASIC2 and ASIC-mediated acidotoxicity
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