HOMER1, HOMER2, and HOMER3: How These Homologs Promote Strong Synaptic Plasticity

Homer Protein Homolog 1, 2, And 3

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983752/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983752/

 

In this post, we will discuss Homer proteins (mainly homer1), their implicated diseases with dysregulation, and some novel ways to help with homeostasis.

Contents:

  1. Basics Homer Protein Homologs
  2. Homer1
  3. What Is Homer1 Dysregulation Involved In?
  4. How To Balance Homer1
  5. Homer2 And Homer3
  6. What Are Homer2 And Homer3 Dysregulations Involved In?
  7. Mechanism Of Action
  8. Genetics
  9. More Research

Basics Of Homer Protein Homologs

The process of learning something new involves a mechanism called "synaptic plasticity":

  1. In the brain, Synapses (the gap between two cells) try to stay in homeostasis (healthy state).
  2. When new environmental changes happen, this causes synapses to grow or shrink (Plasticity).

For example, learning something new involves synapses to grow (via neurotransmitters such as Glutamate, GABA, Dopamine, Acetylcholine, etc) and this creates new connections in the brain. 

After this connection is made, decreased activity (such as sleep) usually allows the synapses to keep the strong connections made, while weak connections get discarded.

This is where the Homer Protein Homolog (HOMER) come into play.

Homer is a family of protein groups that are localized at the end part (postsynaptic density) of neurons.

They contribute to the integrity and proper function of synapses by cleaning and regulating the size of these synapses and keeping the newly built structures strong or discarding the weak ones. 

As a key modulator of synaptic plasticity homeostasis, Homer plays a role in numerous amounts of psychological and physiological processes in the body and brain such as sleep, memory formation, anxiety, fear, addiction and social activity. 

In this post we will mostly be focusing on the Homer's regulation in the nervous system, but Homer proteins are also expressed in the heart, kidney, muscle, ovary, and testicles (to name a few areas). R

Homer1

There are three forms of Homer1: R

  1. Homer1a - short-form
  2. Homer1b - long-form
  3. Ho mer1c - long-form

Homer1 work on synaptic plasticity mainly via calcium and glutaminergic systems. R

What Is Homer1 Dysregulation Involved In?

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469824/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469824/

 
  • Addiction R
  • Alzheimer's Disease - Hypertension may produce lower levels of BDNF and Homer1 R R
  • Amyotrophic Lateral Sclerosis (ALS) - Homer1b/c supresses the action of SOD on protecting neurons from death (via Bax/BCL2) R
  • Anxiety and Autism Reducing Homer1a may improve anxiety levels and social behavior. For example, over-expression of Homer1a (in the amygdala) can induce autism-like behaviors increase anxiety levels. R
  • Bipolar Disorder R
  • Brain Health (Autophagy and Excitotoxicity)
    • Homer1a regulates autophagy of brain cells (via AMPK). R
    • Homer1a protected against NMDA-induced neuronal injury. R
    • Down-regulation of Homer1b/c attenuates glutamate-mediated excitotoxicity through endoplasmic reticulum and mitochondria pathways R
  • Cognitive Function and Disabled Learning/Poor Memory R
    • HOMER1a gene expression is strongly linked with learning and neuronal activity. R
    • Reducing HOMER1a's expression (of binding to mGLUR5) can increase cognitive performance and memory. R
    • Overexpression of Homer 1a impairs memory, while the overexpression of Homer 1c improves memory performance. R
  • Depression and HPA-dysfunction R R
  • Emotion and Fear - Loss of Homer1a causes hyper-emotion in animal models R R
  • Epilepsy R R
    • Homer1a regulates the Endocannabinoid System R
    • Down-regulation of Homer1b/c protects against chemically induced seizures through inhibition of mTOR signaling R
  • Long-Term Potentiation (LTP) - HOMER1a up-regulation can reduce high levels of glutamate synaptic plasticity, thus balancing out memory formation. R R
  • Memory Formation
    • Memory formation and consolidation is a paramount part of sleep that allows for a healthy brain to learn and store new memories.  
    • During the day, there is strong activity in the brain which causes synapses to strengthen (via increased glutamate e.g. AMPA, mGLUR1/5, PKA and reduced Adenosine). R
    • The opposite happens during sleep, where synaptic strength is weakened, in order to allow homeostasis in the brain.
    • Homer1a is regulated by the increased need to sleep, not strictly by time-of day. R 
    • So increased HOMER1a levels may produce benefits during sleep.
    • This is because Homer1a balances out synapses in the brain by weakening unnecessary connections, but keeping the stronger connections intact. R
    • Thus, increasing HOMER1a may improve sleep, while inhibiting HOMER1a may promote wakefulness (Homer1a serves as a molecular integrator of arousal and sleep need through the opposing actions of Noradrenaline and adenosine). R 
    • Lower Homer1a/b/c bound to mGLUR5 = increased cognition (Homer1a/b/c binds to mGLUR5 and inhibits it allowing for decreased synaptic plasticity). R
  • Motivation (via pain/reward) R
  • Neuroinflammation R
    • Inhibiting Homer1a restores mGlu5-mediated Ca2+ signaling and glutamate release and sensitizes astrocytes to apoptosis R
    • Homer1b/c might promote neuronal apoptosis via the Bax/Bcl-2 dependent pathway during neuroinflammation in CNS, and inhibiting Homer1b/c expression might provide a novel neuroprotective strategy against the inflammation-related neuronal apoptosis R
  • Neuropathy - Increased Homer1b/c is seen in neuropathic pain R 
  • Pain R
  • Parkinson's Disease - Loss of homer1 protects Dopamine neurons via calcium homeostasis R
  • Schizophrenia - In the hippocampus there has shown to be increased Homer1a, but decreased home1b/c.  R
  • Traumatic Brain Injury, Stroke, and Hypoxia: R R
    • Downregulation of Homer1b/c protects neurons after traumatic injury R
    • In large-artery atherosclerosis (LAA) strokes, Homer1 and Homer2 are upregulated (possible biomarkers), while Homer3 is unchanged R
    • Kallikrein protects the brain from hypoxia via activation of Homer1b/c-ERK1/2 and Homer1b/c-PI3K-Akt signaling pathways R

How To Balance Homer1

For those that are healthy:

  • Homer1a - decrease HOMER1a during the day, but increase it at night R
  • Homer1c - increase Homer1c for better cognition (esp. if older) R

What May Balance Homer1?

Here are some healthy ways to balance Homer1:

  • CB1 Activation - helps balance HOMER1a R
  • Environmental Enrichment - improves aged hippocampal functions (better learning, memory, LTP, and mGluR5-Homer1c activity) R
  • Learning Something New R
  • Parkin - stabilizes Homer1 R
  • Sleep - maintains healthy HOMER1a production R

What Decreases Homer1?

  • Amphetamines - decreases homer1a R
  • Doxorubicin - reduces Homer1b/c R
  • Electroconvulsive Therapy - during ECT, HOMER1a is increased, while after it decreases
  • Lithium - reduces overactive Homer1b/c R R
  • Norepinephrine - decreases homer1a R
  • Valproic Acid - reduces overactive Homer1b/c R R

What Increases Homer1?

  • Adenosine (A1R agonists) R
  • Antipsychotics - increases HOMER1a  R
  • BDNF - increases HOMER1a R
  • Cocaine - increases HOMER1a R
  • Imipramine - increases HOMER1a R
  • Ketamine - increases HOMER1a  R
  • New Environment - raises Homer1a in forebrain R
  • SIRT1 R
  • Sleep Deprivation - acutely raises HOMER1a R

Homer2 And Homer3

Homer2 and Homer 3 interact with skeletal muscle calcium release (Homer 2 via RYR1 and Homer3 via TRPC1 and RYR1). R

There are two forms of Homer2 and two forms of Homer3

  1. Homer2a and Homer2b R
  2. Homer3a and Homer3b R

What Are Homer2 And Homer3 Dysregulations Involved In?

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679411/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679411/

 

Homer2 and Homer3 play a role in:

  • Alcohol addiction and withdrawal - Homer2 increases in the nucleus accumbens and amygdala (playing a role in addiction) from alcohol consumption, whereas only in the amygdala does it cause anxiety from withdrawal R R
  • Alzheimer's Disease - Homer2 and Homer3 interact with amyloid precursor protein and inhibit Abeta production R R R
  • Autism - Homer3 R
  • Cancer - HOMER2 and MYO18B cooperate together in tumor suppression; Homer3 plays a role in leukemia growth; homer3 also establishes neutrophil polarity R R R
  • Cocaine addiction - Homer2 R R
  • Hearing - Homer2 is required for normal hearing R
  • Memory - loss of homer2 causes alteration of NMDA receptors in hippocampus R
  • Neuropathy - overexpression Homer2b exacerbates neuropathic pain R
  • Stress -Homer2 R

Mechanism Of Action

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714871/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714871/

 
  • All Homer proteins, through their N-terminal domain, bind a specific short proline-rich amino acid sequence found in several signaling proteins: Group1 of metabotropic glutamate receptors (mGluRs); Ca2+-signaling-related proteins, including phospholipase C-ß (PLCß), inositol 1,4,5-trisphosphate receptors, ryanodine receptors, transient receptor potential canonical ion channels; PSD scaffolding proteins, such as Shank component of the NMDA receptor-associated PSD-95 complex. R
  • The binding to these molecules allows Homers to serve as a postsynaptic scaffold that crosslinks and, thus, regulates the functionality of the ligands. R
  • At the onset of sleep or after prolonged wakefulness, NA levels decline and adenosine increases; Homer1a is then targeted to synapses where it binds mGluR1/5 and remodels/activates mGluR1/5(-IP3R complex formation) signaling to drive synapse weakening. R
  • Homer1 interacts with group 1 metabotrophic glutamate receptor (mGluR1 and mGluR5), IP3 receptors (IP3R), Shank, transient receptor potential canonical (TRPC) family channels, arrestin, drebrin, oligophrenin, dynamin3, CENTG1, and ryanodin receptor. R R R

Genetics

HOMER1

rs10942891

  • C Allele - increased risk for hallucinations from L-dopa treatment in PD R

rs2290639

  • AA homozygote - significantly associated with Suicide Attempts in Hong Kong Chinese R

rs4704559

  • A Allele - had 5x increased risk for hallucinations vs non carriers from L-dopa treatment in PD R

rs4704560

  • C Allele - increased risk for hallucinations from L-dopa treatment in PD R

rs474559

  • G allele - have lower prevalence of dyskinesia as it might disrupt the glutamatergic transmission R
  • GG/GA - lower prevalence of dyskinesia from Levodopa in Parkinson's Disease R

rs60029191

  • T alleles - associated with Major Depressive Disorder and Suicide Attempts in Chinese R

rs6871510

  • No allele reported - potential risk factor for the development of cocaine dependence in an African American population R

rs7713917

  • A allele - higher risk for a dysregulation of cognitive and motivational processes by influencing prefrontal activity during anticipation of reward R

More Research

  • In opiate addiction, DRD1 rs265973 genotype correlated with HOMER1b/c levels in the striatum, but not cortex or amygdala. R