Shank protein: Difference between revisions
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<StructureSection load='' size='500' side='right' caption='Structure of Shank Family Proteins, [[]]' scene=''> | <StructureSection load='' size='500' side='right' caption='Structure of Shank Family Proteins, [[]]' scene=''> | ||
[[Image:Shank Schematic.png|150px|left]] [[Shank Family Proteins]] are scaffolding proteins found in the postsynaptic density (PSD) of excitatory synapses. The PSD, a structure within dendritic spines that is associated with the postsynaptic membrane, contains a complex assembly of proteins which organize neurotransmitter receptors, signaling pathways, and regulatory elements within a cytoskeletal matrix.<ref name="Park">PMID:12626503</ref> It aids the appropriate communication of incoming signals to cytoplasmic targets and contributes to neuronal plasticity by readily changing its composition and structure in response to neural activity.<ref name="Baron">PMID:16439662</ref> Shank proteins are believed to function as master organizer of the PSD owing to their ability to recruit and form multimeric complexes with postsynaptic receptors, signaling molecules and cytoskeletal proteins like AMPA, [[Neuroligin-Neurexin | [[Image:Shank Schematic.png|150px|left]] [[Shank Family Proteins]] are scaffolding proteins found in the postsynaptic density (PSD) of excitatory synapses. The PSD, a structure within dendritic spines that is associated with the postsynaptic membrane, contains a complex assembly of proteins which organize neurotransmitter receptors, signaling pathways, and regulatory elements within a cytoskeletal matrix.<ref name="Park">PMID:12626503</ref> It aids the appropriate communication of incoming signals to cytoplasmic targets and contributes to neuronal plasticity by readily changing its composition and structure in response to neural activity.<ref name="Baron">PMID:16439662</ref> Shank proteins are believed to function as master organizer of the PSD owing to their ability to recruit and form multimeric complexes with postsynaptic receptors, signaling molecules and cytoskeletal proteins like AMPA, [[Neuroligin-Neurexin Interaction|Neuroligin]] and NMDA glutamate receptors.<ref name="Durand">PMID:17173049</ref> Within the PSD, there are over 300 individual shank molecules in a single postsynaptic site, representing 5% of the total protein molecules and total protein mass of the PSD.<ref name="Bozdagi">PMID: 21167025</ref> Shanks contain five domains for protein-protein interactions, including an ankyrin repeat domain, used to bind acting regulating proteins, an Src homology 3 (Sh3) domain, used to bind AMPA receptors, a PDZ domain, used to bind G protein coupled receptors, several proline-rich domains , and a C-terminal SAM domain, which is responsible for mediating Shank multimerization.<ref name="Park"/> Functionally, Shank is involved in the maturation and enlargement of dendritic spines and is able to induce spine formation in neurons.<ref name="Durand"/> | ||
Chromosome 22q13 deletion syndrome (22q13DS) is a neurobehavioral syndrome marked by neonatal hyptonia, global developmental delay, and [[Autism|autism spectrum disorder]] features.<ref name="Durand"/> The SHANK3 gene is located within this region of chromosome 22. Studies have revealed that point mutations in SHANK3 can produce the entirety of neurodevelopmental symptoms associated with 22q13DS, accounting for 1% of autism cases.<ref name="Garber">PMID: 17626859</ref> At the molecular level, disruption of the full length Shank3 protein results in reductions in AMPA receptor mediated transmission and spine remodeling.<ref name="Bozdagi"/> Shank3 heterozygous mice, who are haploinsufficient for the Shank3 gene display less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female. Further, knockout mice of Shank have a decreased spine number, a diminished PSD size, decreased levels of GKAP and Homer, and reduced synaptic transmission. Interestingly, overexpression of SHANK3 may also result in an ASD, supporting the hypothesis that Autism is caused by improper Excitatory/Inhibitory neuronal ratios in the brain.<ref name="Bozdagi"/> Measurements of broad miRNA expression levels in Autism patients uncovered dysregulated miRNAs for genes like that of [[MeCP2]], the cause of Rett Syndrome, [[Neurexin-Neuroligin Interaction|NRXN-1]], a gene implicated in ASDs, and Shank3, validating Shank3’s role in autism.<ref>PMID:18563458</ref> Due to the marked reduction in AMPA mediated transmission in Shank3 mutants, compounds that enhance AMPA transmission (AMPAkinses) as potential [[Pharmaceutical Drugs|therapeutic approaches]] to treating some ASDs.<ref name="Bozdagi"/> | Chromosome 22q13 deletion syndrome (22q13DS) is a neurobehavioral syndrome marked by neonatal hyptonia, global developmental delay, and [[Autism|autism spectrum disorder]] features.<ref name="Durand"/> The SHANK3 gene is located within this region of chromosome 22. Studies have revealed that point mutations in SHANK3 can produce the entirety of neurodevelopmental symptoms associated with 22q13DS, accounting for 1% of autism cases.<ref name="Garber">PMID: 17626859</ref> At the molecular level, disruption of the full length Shank3 protein results in reductions in AMPA receptor mediated transmission and spine remodeling.<ref name="Bozdagi"/> Shank3 heterozygous mice, who are haploinsufficient for the Shank3 gene display less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female. Further, knockout mice of Shank have a decreased spine number, a diminished PSD size, decreased levels of GKAP and Homer, and reduced synaptic transmission. Interestingly, overexpression of SHANK3 may also result in an ASD, supporting the hypothesis that Autism is caused by improper Excitatory/Inhibitory neuronal ratios in the brain.<ref name="Bozdagi"/> Measurements of broad miRNA expression levels in Autism patients uncovered dysregulated miRNAs for genes like that of [[MeCP2]], the cause of Rett Syndrome, [[Neurexin-Neuroligin Interaction|NRXN-1]], a gene implicated in ASDs, and Shank3, validating Shank3’s role in autism.<ref>PMID:18563458</ref> Due to the marked reduction in AMPA mediated transmission in Shank3 mutants, compounds that enhance AMPA transmission (AMPAkinses) as potential [[Pharmaceutical Drugs|therapeutic approaches]] to treating some ASDs.<ref name="Bozdagi"/> | ||