Figures & data
Figure 1. Prion protein signaling at the synapse. General: PrPC possesses a normal, physiological activity, which is neuroprotective and is lost upon conversion to PrPSc leading to a loss-of-function phenotype. Secondly in prion disease, the toxic gain-of-function mechanism: PrPSc possesses a novel neurotoxic activity that is independent of the normal function of PrPC. Presynaptic signaling: Prion protein is widely expressed at presynaptic sites. PrPC is involved in vesicle pool maintenance. It potentially contributes to vesicle recycling/cycling leading to distinct availabilities of vesicles and function pool sizes (1) and vesicle recruitment (2). It is further involved in trafficking of a VGCC subunit (α2δ−1) to the membrane, thereby facilitating Ca2+-dependent neurotransmitter release (3). Its interaction with synapsin, a vesicular protein involved in transmitter release, also implicates PrPC in vesicle fusion mechanisms (4). PrPC internalization is dependent upon activity of dynamin I, a key mechano-enzyme involved with the fission of endocytotic vesicles from the plasma membrane (5). Postsynaptic signaling (excitatory or inhibitory): PrPC has been found to interact with several receptors and postsynaptic molecules. It is associated with postsynaptic densities (PSD-95) and has been shown to directly interact with NMDARs (NR2D) and glutamate receptors (GluR6/7) thereby attenuating nNOS/NO-dependent excitotoxicity by inhibiting the receptors. The interaction with the α7nAChR complex promotes receptor signaling. PrPC modulates G-protein coupled receptor signaling (activation of metabotropic glutamate receptor [mGluR1/5] signaling via direct PrP-mGluR interaction) and leads to inhibition of the serotonin 1B receptor (5-HT1BR). All of the above prion protein-mediated functions will ultimately affect synaptic signaling, action potential propagation and physiology with its dysfunction potentially contributing to neurodegenerative phenotypes. Abbreviations: 5-HT1BR – Serotonin 1B receptor, AC – adenylyl cyclase, AP – action potential, AZ – active zone, α7nAChR – α-7 nicotinic acetylcholine receptor, mGluR – metabotropic glutamate receptor, NMDAR – N-methyl-D-aspartate receptor, nNOS – neuronal nitric oxide synthase, NO – nitric oxide, PLC – phospholipase C, RRP – ready releasable pool, RP – reserve pool, VGCC – voltage gated Ca2+ channels.
![Figure 1. Prion protein signaling at the synapse. General: PrPC possesses a normal, physiological activity, which is neuroprotective and is lost upon conversion to PrPSc leading to a loss-of-function phenotype. Secondly in prion disease, the toxic gain-of-function mechanism: PrPSc possesses a novel neurotoxic activity that is independent of the normal function of PrPC. Presynaptic signaling: Prion protein is widely expressed at presynaptic sites. PrPC is involved in vesicle pool maintenance. It potentially contributes to vesicle recycling/cycling leading to distinct availabilities of vesicles and function pool sizes (1) and vesicle recruitment (2). It is further involved in trafficking of a VGCC subunit (α2δ−1) to the membrane, thereby facilitating Ca2+-dependent neurotransmitter release (3). Its interaction with synapsin, a vesicular protein involved in transmitter release, also implicates PrPC in vesicle fusion mechanisms (4). PrPC internalization is dependent upon activity of dynamin I, a key mechano-enzyme involved with the fission of endocytotic vesicles from the plasma membrane (5). Postsynaptic signaling (excitatory or inhibitory): PrPC has been found to interact with several receptors and postsynaptic molecules. It is associated with postsynaptic densities (PSD-95) and has been shown to directly interact with NMDARs (NR2D) and glutamate receptors (GluR6/7) thereby attenuating nNOS/NO-dependent excitotoxicity by inhibiting the receptors. The interaction with the α7nAChR complex promotes receptor signaling. PrPC modulates G-protein coupled receptor signaling (activation of metabotropic glutamate receptor [mGluR1/5] signaling via direct PrP-mGluR interaction) and leads to inhibition of the serotonin 1B receptor (5-HT1BR). All of the above prion protein-mediated functions will ultimately affect synaptic signaling, action potential propagation and physiology with its dysfunction potentially contributing to neurodegenerative phenotypes. Abbreviations: 5-HT1BR – Serotonin 1B receptor, AC – adenylyl cyclase, AP – action potential, AZ – active zone, α7nAChR – α-7 nicotinic acetylcholine receptor, mGluR – metabotropic glutamate receptor, NMDAR – N-methyl-D-aspartate receptor, nNOS – neuronal nitric oxide synthase, NO – nitric oxide, PLC – phospholipase C, RRP – ready releasable pool, RP – reserve pool, VGCC – voltage gated Ca2+ channels.](/cms/asset/623b7fad-9202-4719-ad65-bc8a3c49dcc9/kcib_a_1063753_f0001_oc.gif)