Receptor Subtypes and Signal Tranduction

JAX/STAT

• janus kinase(JAK)

• signal transducer and activator of transcription(STAT)

highly efficient and regulated system dedicated to gene transcription

JAK/STAT signaling pathway

1. ligand-mediated receptor dimerization

2. JAK binds to the dimerized receptor

3. JAK is phosphorylated

4. JAK phosorylates tryosine residues

5. STATS recruited and JAK-mediated phosphorylation

6. Dimerization of STATs

7. Translocation into nucleus

Outcome of JAK/STAT signaling

• Growth factors:cell proliferation, differentiation, survival

• Cytokines: promote wound healing and regulate neuronal excitability

• Hormones: regulate behavior and physiology

Adult Neurogenesis:Dentate Gyrus

subgranular zone is below dentate gyrus

has radial glial cells, can be stimulated by entorhinal cortex or contralateral DG to induce neurogenesis

What does BMP, Notch, GABA do?

inhibits neural differentiation

What does Wnt,Shh, IGF do?

stimulate differentiation

What does BDNF do to the Neuroblast?

chemoattractant and help migration

What does Wnt do to the Neuroblast?

make it neurons

What does Reelin and GABA do to the Neuroblast?

stops movement and inhibits neural differentiation

FGF as a regulator of adult neurogenesis

• signals through JAK/STAT pathway

• upregulated after injury, stress, repeated stimulation

• can reverse age-related decline in hippocampus neurogenesis

Multiple Sclerosis

• results in slow depletion and loss of myelin

• increase in microglia and increased levels of antibodies targeting oligodendrocytes for degradation

Microglia in MS engage in complement signaling

C1q

C3

C5b-9

C1q

microglial tag

C3

directly activate microglial cells for engulfment

C5b-9

membrane attack complex

expressed as a result of C3R activation

in oligodendrocytes

Complement signaling activates Microglia via JAK/STAT

CRS activates STAT1 and STAT3

measured transcription factors in microglia associated with inflammation and complement signaling

Outcomes of Microglial C3R signaling through JAK/STAT

normalizes system

Cytokine signaling via JAK/STAT

• creation of more inflammatory cytokines

• initiate microgliosis

• differentiation of microglia

TRK(Trks)

• enzyme-linked receptors but have a kinase domain

  • TRk receptors exist as monomer in the membrane and must be stablized by the ligand

  • when receptor dimierizes, auto phosphorylates its tyrosine residue (no extra enzyme required)

  • Trk can activate 3 different pathways

What is the dominant form of Trk

TrkB is the dominant form

TrkB signaling partners compete for tyrosine residue

PI3K and Ras pathways compete for binding at residue 515

produce different effects

TrkB signaling partners compete for tyrosine residue

efffect on neurons

MAPK depolarizes neurons

Akt increases inhibitory signaling

TrkB signaling partners compete for tyrosine residue

efffect on behavior

MAPK promotes fear, anxiety, depressive-like behaviors

Akt produces anti-depressant effects

BDNF in stress

• Amygdala is critical in response to stress

  • involved in emotional processing

  • encoded intensity of an emotional stimulus

BDNF plays a role in synaptic strenghtening, enuronal grwoth and survival

• implicated in PTSD and anxiety

• stress impacts BDNF levels

stress vs behavior

behavior during defeat is predictive of the behvaioral outcomes following stress

how does stress relate to TrkB

passive coping is associated with increased phosphorylation of TrkB, MAPK, and ERK1/2

• depolarized resting membrane potential

• acquisition and expression of fear

• emergence of anxiety and depressive-like behavior

Activation of TRKB receptors does not mean all pathways are active

Stress on BDNF

• chronic stress the hippocampus atrophies

Stress

• reduces BDNF

• impairs adult neurogenesis

• reduces serotonin in favor of other inhibitory transmitters

stress and depression

anxiety and depressive like behaviors have been linked to hippocampal function

Intracellular/nuclear receptors

• 48 nuclear receptors into 7 families

• ligand must cross cell membrane

  • ligands are lipophilic

• translocate to the nucleus to affect gene transcription

Estrogen

signals via multiple pathways including intracellular mechanisms

• produces effects on gene transcription

• other pathways do not directly affect genes

estrogen genomic effects regulate

• neurogenesis

• synaptic plasticity

• neuronal excitability

Sex differences in Dentate gyrus

males have more neural stem cells in the hippocampus

• dorsal-spatial memory and cognition

• ventral- emotional processing and anxiety

Adult neurogenesis in males vs females

• faster in males

  • when neuronal stem cells begin proliferating, they reach maturity more rapidly in males than fmales

• suggests that adult neurogenesis is eitehr

  • under tighter regulation in females

  • more easily stimulated in males

effect of stress on females

• TMT-chemical odorant in predators

  • potent stressors in rodents

Males show stronger hippocampal effects than females

females are more resilient to hippocampal