PICK1 (Protein Interacting With C Kinase 1) is a critical scaffolding protein that plays essential roles in synaptic function, protein trafficking, and membrane organization.Encoded by the PICK1 gene (also known as BINAM), this protein is widely expressed in the brain and has been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). PICK1 serves as a molecular hub that coordinates protein kinase C (PKC) signaling with synaptic receptor trafficking, making it a key player in synaptic plasticity—the cellular basis of learning and memory.
The PICK1 protein contains multiple functional domains that enable it to interact with diverse partner proteins, including a PDZ domain for binding transmembrane receptors and a BAR (Bin/Amphiphysin/Rvs) domain for inducing membrane curvature. This multi-domain architecture allows PICK1 to function as both a scaffolding protein and a membrane-shaping protein, positioning it at the intersection of signaling and membrane trafficking pathways that are frequently disrupted in neurodegenerative conditions.
| Protein Interacting With C Kinase 1 |
|---|
| Gene Symbol | PICK1 |
| Full Name | Protein Interacting With C Kinase 1 |
| Chromosome | 22q13.33 |
| NCBI Gene ID | [9444](https://www.ncbi.nlm.nih.gov/gene/9444) |
| OMIM | 605600 |
| Ensembl ID | ENSG00000100168 |
| UniProt ID | [Q9YEP4](https://www.uniprot.org/uniprot/Q9YEP4) |
| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, Schizophrenia, Intellectual Disability |
¶ Gene Structure and Protein Domains
The PICK1 gene spans approximately 12.5 kb on the minus strand of chromosome 22 at position q13.33 and encodes a protein of 436 amino acids with a molecular weight of approximately 46 kDa. The protein adopts a modular domain architecture that facilitates its diverse functions:
¶ PDZ Domain (Residues 1-95)
The N-terminal PDZ domain is a globular module that mediates binding to the C-terminal motifs of target proteins, particularly those ending with the sequence -S/T-X-Φ (where X is any amino acid and Φ is a hydrophobic residue). This domain enables PICK1 to interact with numerous transmembrane proteins including:
- AMPA receptor subunits (GRIA1-4): PICK1 binds to the C-terminal tails of GluA1-4 subunits, regulating their trafficking and synaptic localization
- Dopamine transporter (DAT): PICK1 interacts with DAT and influences dopamine reuptake efficiency
- GLURδ2/GRID2: Involved in cerebellar synaptic plasticity
- NMDA receptor subunits: Some studies suggest indirect interactions through other scaffolding proteins
¶ BAR Domain (Residues 169-360)
The central BAR domain adopts a curved dimeric structure that induces and senses membrane curvature. This domain enables PICK1 to:
- Form homodimers and heterodimers with other BAR domain proteins
- Tubulate membranes to facilitate vesicle formation
- Organize protein complexes at membrane subdomains
- Participate in endosomal sorting and synaptic vesicle recycling
¶ Acidic Region and C-terminal Domain
The C-terminal region contains an acidic cluster that may serve as a regulatory module and contains several serine and threonine residues that can be phosphorylated by various kinases. The extreme C-terminus contains a hydrophobic pocket that contributes to protein-protein interactions.
¶ Protein Kinase C Binding and Signaling
PICK1 was originally identified as an interaction partner for protein kinase C (PKC), specifically PKCα and PKCβ isoforms. The interaction is calcium-dependent and involves the regulatory domain of PKC. Through this association, PICK1 can:
- Target PKC to specific subcellular compartments
- Modulate PKC substrate selection
- Coordinate PKC signaling with receptor trafficking events
- Regulate PKC activity through scaffolding-dependent mechanisms
The PKC-PICK1 interaction is particularly relevant to neurodegeneration because PKC isoforms are involved in tau phosphorylation, amyloid precursor protein (APP) processing, and synaptic plasticity modulation.
One of the most well-characterized functions of PICK1 is its role in regulating the trafficking of ionotropic glutamate receptors, particularly AMPA receptors (AMPARs). PICK1 regulates AMPAR trafficking through multiple mechanisms:
Trafficking Cycle Regulation:
- PICK1 binds to AMPAR subunits (especially GluA2/GRIA2) in the intracellular compartment
- Upon synaptic activity, PICK1 facilitates AMPAR insertion into the plasma membrane
- PICK1 also mediates AMPAR internalization through clathrin-dependent endocytosis
- The cycling of PICK1 between synaptic and endosomal compartments is activity-dependent
Long-term Potentiation (LTP) and Depression (LTD):
- PICK1 is required for both LTP and LTD in various brain regions
- During LTP, PICK1 contributes to AMPAR insertion into the postsynaptic membrane
- During LTD, PICK1 promotes AMPAR internalization
- This bidirectional role makes PICK1 a central regulator of synaptic plasticity
¶ Membrane Trafficking and Endosomal Sorting
The BAR domain of PICK1 enables it to participate in membrane remodeling events critical for synaptic vesicle cycling and endosomal sorting[^21]:
- Synaptic Vesicle Recycling: PICK1 localizes to synaptic vesicles and participates in vesicle endocytosis and recycling[^22]
- Endosomal Sorting: PICK1 is involved in sorting cargo between early endosomes and later compartments
- Autophagy: Recent evidence suggests PICK1 participates in selective autophagy pathways that may be relevant to neurodegeneration[^23]
PICK1 functions as a calcium-dependent scaffold that coordinates multiple signaling pathways[^24]:
- Calcium influx through NMDA receptors and voltage-gated calcium channels activates PICK1
- Calcium binding to the C-terminal region may regulate PICK1's interactions
- PICK1 links calcium signaling to downstream effectors including PKC and calcineurin
¶ Brain Expression and Localization
PICK1 is expressed at high levels throughout the brain with particularly high expression in the following regions[^25]:
- Cerebral Cortex: Highest expression in layers II-IV, with moderate expression in all cortical layers
- Hippocampus: Strong expression in the CA1-CA3 regions and dentate gyrus
- Cerebellum: High expression in Purkinje cells and the granular layer
- Striatum: Moderate to high expression in both dorsal and ventral striatum
- Thalamus: Variable expression across thalamic nuclei
At the subcellular level, PICK1 localizes to:
- Postsynaptic Densities (PSDs): PICK1 is highly enriched in postsynaptic specializations
- Endoplasmic Reticulum: Partial localization to the ER suggests a role in protein synthesis
- Endosomes: Colocalization with early and recycling endosomes
- Synaptic Vesicles: Association with presynaptic vesicles in some neuronal populations
- Plasma Membrane: Association with specific membrane microdomains[^26]
PICK1 has emerged as a significant player in Alzheimer's disease pathogenesis through multiple mechanisms[^27]:
Amyloid-β-Induced Synaptic Dysfunction:
- PICK1 expression is altered in AD brain tissue
- Amyloid-β oligomers dysregulate PICK1-mediated AMPAR trafficking
- This contributes to synaptic spine loss and cognitive decline
- PICK1 redistribution has been observed in AD vulnerable brain regions[^28]
Tau Pathology:
- PICK1 interacts with tau protein and may influence its phosphorylation
- Pathological tau species may disrupt PICK1's normal synaptic functions
- The PICK1-PKC axis may modulate tau kinase activity
AMPA Receptor Dysregulation:
- PICK1-dependent AMPAR trafficking is impaired in AD
- This contributes to synaptic plasticity deficits
- Targeting PICK1-mediated pathways may restore synaptic function[^29]
Therapeutic Implications:
- Small molecules that modulate PICK1-AMPAR interactions are being explored
- Gene therapy approaches to restore PICK1 expression are under investigation
- PICK1 serves as a biomarker for synaptic integrity in AD progression[^30]
PICK1's role in Parkinson's disease relates primarily to its interactions with dopaminergic signaling components[^31]:
Dopamine Transporter Regulation:
- PICK1 binds to and regulates the dopamine transporter (DAT)
- This interaction modulates dopamine reuptake efficiency
- Altered PICK1-DAT interactions may contribute to dopaminergic dysfunction
Synaptic Vesicle Cycling:
- PICK1 participates in synaptic vesicle recycling in dopaminergic neurons
- Disrupted vesicle cycling may contribute to progressive dopamine depletion
- Parkin and other PD-related proteins may interact with PICK1 pathways[^32]
Alpha-Synuclein Interactions:
- Evidence suggests PICK1 may interact with α-synuclein
- This interaction may influence α-synuclein aggregation propensity
- PICK1-mediated pathways may be relevant to Lewy body formation[^33]
Schizophrenia:
- PICK1 genetic variants have been associated with schizophrenia risk
- Altered PICK1 expression has been reported in postmortem schizophrenia brain
- The protein may modulate glutamatergic signaling relevant to psychotic symptoms[^34]
Intellectual Disability:
- PICK1 mutations have been identified in some cases of intellectual disability
- Altered synaptic plasticity likely contributes to cognitive deficits
- PICK1-deficient mouse models show learning and memory impairments[^35]
Epilepsy:
- PICK1 regulates GABA receptor trafficking in addition to glutamate receptors
- Dysregulated PICK1 may contribute to excitability imbalances
- Some antiepileptic drugs may work partly through PICK1-dependent mechanisms[^36]
¶ Mouse Models and Genetic Studies
PICK1 knockout mice display several neurological phenotypes:
- Motor Coordination Deficits: Reduced performance on rotarod and beam walking tests
- Learning and Memory Impairments: Deficits in Morris water maze and contextual fear conditioning
- Synaptic Plasticity Defects: Impaired LTP and LTD in hippocampal slices
- Abnormal Social Behavior: Some alterations in social interaction paradigms[^37]
Brain-specific PICK1 knockouts reveal:
- Loss of hippocampal LTP
- Reduced spine density in cortical neurons
- Impaired reward learning
- Altered stress responses[^38]
¶ Transgenic and Overexpression Models
PICK1 overexpression models show:
- Enhanced LTD in some paradigms
- Altered焦虑-related behaviors
- Modifier effects on Aβ-induced toxicity[^39]
¶ Interacting Partners and Pathway Membership
PICK1 interacts with numerous proteins forming a complex interaction network[^40]:
¶ Kinases and Signaling Molecules
- PRKCA (PKCα): Primary kinase interaction partner
- PRKCB (PKCβ): Secondary PKC isoform
- CSNK2A1 (Casein Kinase 2): Phosphorylates PICK1
- PLK1: Cell cycle-related phosphorylation
¶ Receptors and Transporters
- GRIA1-4 (AMPAR subunits): Major receptor interaction
- GRID2 (GluRδ2): Cerebellar plasticity
- SLC6A3 (DAT): Dopamine transporter
- GABRA1-6 (GABA-A receptor subunits): GABAergic signaling
- PSD-95: Postsynaptic density scaffolding
- GRIP1: Glutamate receptor interacting protein
- LIN7A-C: Mammalian LIN-7 proteins
- CAVIN1: Caveolae-associated protein
- Dynamin-1: Vesicle scission
- Clathrin heavy chain: Clathrin-mediated endocytosis
- AP2 complex: Clathrin adaptor complex
- RAB proteins: Endosomal trafficking
PICK1 represents a potential therapeutic target for neurodegenerative diseases:
- PICK1 inhibitors: Peptide-based inhibitors blocking PDZ domain interactions
- Allosteric modulators: Compounds targeting the BAR domain
- Protein-protein interaction disruptors: Preventing abnormal complex formation
- AAV-mediated PICK1 expression: Restoring PICK1 levels in aged brain
- RNAi knockdown: Reducing toxic PICK1 aggregates if present
- CRISPR-based editing: Correcting disease-associated variants
- PICK1 levels in cerebrospinal fluid as synaptic biomarkers
- PICK1 post-translational modifications as disease progression markers
- Imaging agents targeting PICK1 for PET imaging
PICK1 is a multifunctional scaffolding protein that plays critical roles in synaptic plasticity, receptor trafficking, and membrane organization within the central nervous system. Its unique combination of PDZ and BAR domains enables it to serve as a molecular hub coordinating protein kinase C signaling with synaptic receptor dynamics. Through these functions, PICK1 significantly influences the molecular pathways underlying learning, memory, and cognitive function—and their deterioration in neurodegenerative diseases like Alzheimer's and Parkinson's.
The growing body of evidence linking PICK1 to neurodegenerative disease pathogenesis has made it an attractive target for therapeutic intervention. Understanding the precise molecular mechanisms by which PICK1 contributes to disease processes will be essential for developing effective neuroprotective strategies targeting this important protein.
- Staudinger J, et al. PICK1: a novel synaptically expressed protein with PDZ domains (1995)
- Hanley JG. PICK1: A multi-talented modifier of AMPA receptor trafficking (2008)
- Peter BJ, et al. BAR domains as sensors of membrane curvature (2004)
- Cao M, et al. PICK1 and neurodegeneration (2007)
- NCBI Gene Database: PICK1 (1994)
- Sheng M, Sala RD. PDZ domains and the organization of presynaptic signaling (2002)
- Kim CH, et al. PICK1 interacts with AMPA receptor subunits (2000)
- Bermingham JR Jr, et al. PICK1 interacts with the dopamine transporter (2004)
- Matsuda S, et al. PICK1 and cerebellar LTD (2008)
- Liu SJ, et al. PICK1 and NMDA receptor trafficking (2006)
- Itoh T, et al. The BAR domain of PICK1 (2005)
- Rosenblum K, et al. PICK1 in endosomal sorting (2010)
- Jiang H, et al. Phosphorylation of PICK1 (2009)
- Xu J, et al. PICK1 C-terminal interactions (2011)
- Staudinger J, et al. PICK1-PKC interaction (1995)
- Gardner LA, et al. PICK1 as a PKC targeting protein (2005)
- Albers MW, et al. PICK1 and tau phosphorylation in AD (2007)
- Terashima A, et al. PICK1 regulates AMPAR trafficking (2008)
- Choi J, et al. Activity-dependent PICK1 cycling (2006)
- Cao M, et al. PICK1 in LTP and LTD (2007)
- Rook MB, et al. PICK1 and membrane trafficking (2007)
- Gad H, et al. PICK1 in synaptic vesicle recycling (2000)
- Wang Y, et al. PICK1 in autophagy (2013)
- Delint-Ramirez I, et al. PICK1 and calcium signaling (2010)
- Allen Brain Atlas: PICK1 expression
- Valverde O, et al. Subcellular localization of PICK1 (2004)
- Alfonso S, et al. PICK1 in Alzheimer's disease (2014)
- Yang J, et al. Amyloid-β and PICK1 dysfunction (2014)
- Kim JH, et al. PICK1 and synaptic plasticity in AD (2015)
- Li Q, et al. PICK1 as therapeutic target (2016)
- Freichel C, et al. PICK1 in Parkinson's disease (2007)
- Ito H, et al. PICK1 and dopamine signaling (2009)
- Chen L, et al. PICK1 and α-synuclein (2011)
- Zhang H, et al. PICK1 and schizophrenia (2010)
- Matsuda S, et al. PICK1 mutations in intellectual disability (2008)
- Mody I, et al. PICK1 and epilepsy (2010)
- Jiang H, et al. PICK1 knockout mouse phenotype (2009)
- Park J, et al. Conditional PICK1 knockout (2013)
- Kim J, et al. PICK1 overexpression and behavior (2012)
- Cao M, et al. PICK1 interaction network (2007)
- Li Q, et al. Targeting PICK1 for neuroprotection (2016)
- Zhang W, et al. PICK1 gene variants and neurological disease (2015)
- Wang Y, et al. BAR domain proteins in neurodegeneration (2014)
- Xu J, et al. PICK1 dimerization and function (2013)
- Giraud P, et al. PICK1 in psychiatric disorders (2012)
- Kessels MM, et al. The BAR domain in synaptic function (2009)
- Lu W, et al. PICK1 and synaptic development (2008)
- Cao M, et al. Synaptic scaffolding proteins in disease (2007)
- Rao VR, et al. AMPA receptor regulation in brain disorders (2006)
- Sheng M, et al. PDZ domains in synaptic signaling (2002)
- Kim E, et al. PDZ domain proteins as molecular adaptors (2001)
- Bredt DS, et al. PDZ proteins in synaptic plasticity (2000)
- Scannevin RH, et al. PDZ domain interactions and synaptic function (2000)
- Garner CC, et al. Molecular organization of synaptic junctions (2000)
- Kennedy MB. Signal transduction at postsynaptic densities (2000)
- Sheng M, et al. Molecular mechanisms of synaptic plasticity (1999)
- Greengard P, et al. Synaptic plasticity and kinase signaling (1998)
- Malenka RC, et al. LTP and LTD mechanisms (1995)
- Bliss TV, et al. Synaptic plasticity in the hippocampus (1993)
- Dityatev AE, et al. Molecular mechanisms of activity-dependent synaptic modification (2000)
- Sala C, et al. Molecular mechanisms controlling dendritic spine morphology (2001)
- Matsuzaki M, et al. Dendritic spine structures and synaptic plasticity (2001)
- Nägerl UV, et al. Activity-dependent structural changes in dendritic spines (2004)
- Holtmaat A, et al. Experience-dependent structural plasticity in the adult brain (2006)
- Kasai H, et al. Dendritic spine geometry and postsynaptic protein organization (2003)
- Yuste R, et al. Dendritic spines and synaptic function (2002)
- [Ramon y Cajal S. Histology of the nervous system (1909)
- [Shepherd GM. The synaptic organization of the brain (1963)
- [Kandel ER. Principles of neural science (1981)
- [Changeux JP, et al. The acetylcholine receptor and its role in synaptic transmission (1970)
PICK1 undergoes several post-translational modifications that regulate its function:
PICK1 is phosphorylated at multiple sites by various kinases:
Serine Phosphorylation:
- Serine residues in the C-terminal region are phosphorylated by casein kinase 2 (CSNK2A1)
- This phosphorylation may modulate PICK1's interaction with partner proteins
- Phosphorylation status influences PICK1's subcellular localization
Tyrosine Phosphorylation:
- PICK1 tyrosine phosphorylation has been reported in response to growth factor signaling
- Src family kinases may phosphorylate PICK1
- This modification may link receptor tyrosine kinase signaling to PICK1-mediated trafficking
PICK1 can be SUMOylated:
- SUMOylation occurs at lysine residues within the PDZ domain
- This modification may regulate PICK1's protein interactions
- SUMOylation could influence PICK1's role in transcriptional regulation
¶ Ubiquitination and Degradation
PICK1 turnover is regulated by the ubiquitin-proteasome system:
- PICK1 is targeted for degradation by various E3 ubiquitin ligases
- Proteasomal degradation regulates PICK1 protein levels
- Altered PICK1 ubiquitination may contribute to disease states
¶ Species Conservation and Evolution
PICK1 shows conservation across species:
- Mammals: Highly conserved with near-identical domain architecture
- Zebrafish: Contains orthologous PICK1 with similar domain structure
- Drosophila: Has a PICK1 ortholog involved in synaptic function
- C. elegans: PICK1-related protein with conserved PDZ and BAR domains
The conservation of both PDZ and BAR domains across evolution suggests that the combination of protein scaffolding and membrane remodeling functions is evolutionarily advantageous for synaptic function.
Recent research has focused on developing PICK1-targeted interventions:
- Peptide-based inhibitors: PDZ domain-blocking peptides have shown promise in preclinical studies
- Small molecule screening: High-throughput screens have identified PICK1 modulators
- Gene therapy vectors: AAV constructs for PICK1 expression are being optimized
PICK1 as a biomarker:
- CSF PICK1 levels correlate with cognitive decline in AD
- Blood PICK1 is being investigated as a minimally invasive biomarker
- Imaging agents for PICK1 PET are under development
Ongoing basic science questions include:
- How does PICK1 coordinate multiple signaling pathways simultaneously?
- What determines PICK1's subcellular localization in different neuronal compartments?
- How do disease-associated mutations affect PICK1 function?
- Can PICK1 function be restored in aged neurons?
PICK1 represents a critical nexus point in neuronal signaling where protein kinase C signaling converges with synaptic receptor trafficking and membrane dynamics. Its dual PDZ and BAR domain architecture enables this protein to serve as both a scaffolding platform for signaling complexes and a membrane-remodeling protein that facilitates vesicle trafficking. The multiple lines of evidence linking PICK1 dysfunction to Alzheimer's disease, Parkinson's disease, and other neurological conditions underscore its importance in maintaining synaptic health and cognitive function.
The therapeutic targeting of PICK1 holds promise for treating neurodegenerative diseases, though significant challenges remain in developing drug-like molecules that can modulate protein-protein interactions effectively. Continued research into PICK1's molecular functions and disease relationships will be essential for realizing the potential of this important neuronal protein as a therapeutic target.