Lecture 15: Receptor Subtypes and Signaling Pathways

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Defining characteristics of receptors

1. Ligand recognition and binding

2. Signal transduction

What steps have amplification?

1. Receptor → G-proteins

2. Adenylyl cyclase → Cyclic AMP

3. Protein kinases → Phosphates transferred to target proteins

Biggest 2 classes of neuroreceptors

1. Transmembrane

2. Intracellular

Transmembrane neuroreceptors

• Ionotropic linked to ion channels

• Metabotropic linked to second messengers like GPCRs and enzyme-linked receptors

Intracellular receptors are…

Nuclear and Cytosolic

Ionotropic mechanism and speed

Flow of ions in msec

GPCR mechanism and speed

Second messengers in seconds

Enzyme linked mechanism and speed

Activation of kinases in minutes

Intracellular mechanism and speed

Act of transcription factors in hours

AMPA, NMDA, and GABA-A are examples of…

Ionotropic

GABA-B, dopamine D1/D2 are examples of…

GPCR

TrkA and insulin are examples of…

Enzyme-linked receptors

Estrogen and glucocorticoids are an example of…

Intracellular

GPCRs are categorized based on…

Similarities

Characteristic of receptor tyrosine kinases

Growth factors and insulin

What do EL receptors contain?

A kinase domain

How does the kinase domain activate?

Autophosphorylation which is ATP dependent

RTKs traditionally signal through what three pathways

1. Phophoinostiol 3 kinase

2. Ras

3. Phospholipase C

What is TrkB?

Tyrosine receptor kinase B

What is special about residue 515?

Two signaling pathways compete for this site

What two signaling pathways compete for residue 515?

Akt and MAPK

MAPK promotes

fear, anxiety and depressive like behaviors

Akt produces

Anti-depressant effects

Higher activation of the amygdala results in…

BDNF production making more stress related connections

Passing coping is associated with..

Increased phosphorylation of TrkB, MAPK, and ERK1/2

Activation of TrkB receptor does or does not mean all pathways are active?

Does not

What are considered to be Cytokine Receptors?

1. Receptors DONT have a kinase domain

2. Must be associated with kinase (JAK or TYK2)

3. Kinases phosphorylate and activate other proteins

Ligands must cross the cell membrane in what type of receptors?

Intracellular/Nuclear

What are 3 methods of translocation to the nucleus to affect gene transcription?

1. DNA methylation

2. Histone acetylation

3. Activate/inhibit transcription

arcuate nucleus regulates what? Ventreromedial nucleus regulates what?

Hunger eating, ceasing hunger/eating

Lesions to the ARC and VMH have different effects on…

Males vs females

More DNA methylation occurs in…

Males with ARC/VMH lesions

What are Grs?

Glucocorticoid receptors

What are MRs?

Mineralcoriticoid receptor

Grs are for…

Negative feedback on stress hormones, regulates motivation and arousal, promotes recovery from stress

MRs are for….

Memory consolidaiton and autonomic regulation

How might a drug that blocks ligand binding to a receptor affect CNS signaling?

• It would inhibit receptor activation, preventing signal transduction and biological effects.  

Compare how receptors convert external signals into internal cellular changes.

Receptors bind ligands, undergo conformational change, and activate intracellular proteins, leading to signal cascades.

Why is signal amplification critical in the CNS, and how do receptors contribute to this process?

Amplification ensures that small stimuli can produce large, coordinated effects. Receptors trigger cascades that exponentially increase the signal.

How do metabotropic receptors differ from ionotropic receptors?

Metabotropic receptors use second messengers and G-proteins, while ionotropic receptors directly open ion channels

• If a neurotransmitter activates a GPCR, what downstream effects might be triggered?

Activation of second messengers like cAMP or IP3, changes in gene expression, or enzyme activity.

Analyze why GPCRs are more diverse than ionotropic receptors.

GPCRs have many structural families and can trigger multiple intracellular cascades via different G-protein subunits.

Why might a neuron express both ionotropic and metabotropic receptors for the same neurotransmitter?

To allow both fast (ionotropic) and modulatory (metabotropic) responses for precise control of activity.

What activates receptor tyrosine kinases (RTKs)?

Ligand binding and autophosphorylation.

: What are the three major signaling pathways activated by RTKs?

PI3K, Ras, and PLC pathways.

How does phosphorylation at residue 515 of TrkB influence behavior?

It determines whether MAPK or Akt pathways dominate, influencing emotional and stress-related behaviors.

Why might activating the same TrkB receptor produce different behavioral outcomes?

Different downstream pathways (MAPK vs. Akt) compete for activation, leading to distinct outcomes.

How could targeting TrkB signaling be used therapeutically in mood disorders?

Enhancing Akt signaling or inhibiting MAPK signaling could promote antidepressant effects.

What kinase families do cytokine receptors associate with?

JAK and TYK2.

Why are cytokine receptors considered enzyme-linked even though they lack intrinsic kinase activity?

They recruit kinases like JAK to perform signaling functions.

What would happen if JAK function were blocked in the brain?

STATs wouldn't be activated, impairing cytokine signaling and gene regulation.

Compare the signaling efficiency between RTKs and cytokine receptors.

RTKs act more directly via intrinsic kinases, while cytokine receptors rely on associated kinases, possibly making them slower or more regulated.

Evaluate the potential for JAK/STAT pathway modulation as a treatment for neuroinflammation.

Targeting JAK/STAT could reduce cytokine-driven inflammation in the brain, potentially treating conditions like multiple sclerosis or depression.

Where are nuclear receptors located before activation?

In the cytoplasm or nucleus.

What type of ligands typically bind nuclear receptors?

Lipophilic ligands like steroid hormones.

How does estrogen receptor activation affect the brain?

It regulates neurogenesis, synaptic plasticity, and gene transcription.

Contrast genomic and non-genomic effects of intracellular receptor signaling.

Genomic effects alter gene transcription; non-genomic effects act through second messengers and cytoplasmic signaling.

Why might two brain regions with the same estrogen receptor show different responses to activation?

Differences in DNA methylation, cofactor availability, and local epigenetics lead to region-specific outcomes.

What brain regions are associated with ERα regulation of hunger and body temperature?

The arcuate nucleus (ARC) and ventromedial hypothalamus (VMHvI).

Why are the ARC and VMHvI considered sexually dimorphic?

They show differences in ERα expression and function between sexes.

If ERα expression increases in the VMHvI, what might be the effect on energy regulation?

It may reduce food intake or alter thermogenesis.

How can methylation patterns influence receptor signaling outcomes?

Methylation can alter receptor expression or function, changing how cells respond to hormones.

Propose a reason why activation of the same receptor might produce opposite effects in two brain regions.

Regional co-regulators, receptor variants, and epigenetic marks may interact differently with the receptor, leading to distinct outcomes.