Emma's Patho Pharm Introduction to Receptor Theory

What characteristic do these details fall under?

- Fit into the receptor binding pocket

- Permeability: smaller -> easier membrane passage - Selectivity: larger -> more specific interactions

Molecular Size

What characteristics do these details fall under?

- Lock-and-Key fit with receptor

- Induced fit: conformational change

- Stereochemistry: enantiomer specificity

Molecular Shape

Molecular Size and Shape will have an impact on….

Receptor Binding

What are the four receptor structures & classes?

Ligand-Gated Ion Channels, GPCRs, Enzyme-Linked Receptors, and Intracellular Receptors

Transmembrane protein that forms an ion-conducting pore in the cell membrane

- it opens in response to the binding of a specific chemical signal (ligand), such as a neurotransmitter. (ex. Nicotinic ACh Receptor)

Ligand Gated Ion Channel (LGIC) (Inotropic receptors)

What key feature of a ligand-gated ion channel (LGIC) is described?

- Triggered by extracellular ligand binding to specific receptor sites on the channel protein

Activation

What key feature of a LGIC is described?

- Allows selective ions (e.g., Na+, K+, Ca2+, Cl-) to pass through the membrane

Function

What key feature of a LGIC is described?

- Mediates fast synaptic transmission

- changes in membrane potential occur within milliseconds

Speed

What key feature of a LGIC is described?

- Different LGICs are selective for specific ions and are activated by specific ligands

Specificity

Ligand-Gated Ion Channels are direct/indirect transporters (fast)

direct

G Protein-Coupled Receptors (metabotropic) are direct/indirect transporters (slow)

indirect

What are three examples of LGICs?

Nicotinic acetylcholine receptor (nAChR), GABA-A Receptor, and NMDA Receptor

What is a LGIC that is a Na+/K+ channel that is activated by acetylcholine?

Nicotinic Acetylcholine Receptor (nAChR)

What is a LGIC that is a Cl- Channel activated bt y-aminobutyric acid?

GABA-A Receptor

What is a LGIC that is a Ca2+/Na+ channel activated by glutamate and glycine?

NMDA Receptor

What is an example of a benzodiazepine? (GABA-A Receptor)

Xanax

• Diverse family of cell surface receptors

• - Relay signals from the outside to the inside of a cell

• - Vast array of physiologic processes

G Protein-Coupled Receptors (GPCRs)

• Single polypeptide chain with 7 transmembrane alpha-helices

• - Extracellular domain: contains the ligand-binding site

• - Intracellular domain: couples to heterotrimeric G proteins

Structure of GPCRs: beta-adrenergic receptors

What are the three main subtypes of beta-adrenergic receptors?

B1, B2, and B3

Predominantly in the heart; increases heart rate and contractility

B1

In smooth muscle (bronchi, vasculature); causes relaxation

B2

In adipose tissue; stimulates lipolysis

B3

7-TMS (transmembrane spanning domains) G-Protein Coupled Receptors

- Receptor is ______ -> a and b subunits ______, each activating a separate target

activated; dissociate

7-TMS/G-Protein Coupled Receptors

- the alpha subunit swaps ____ for ____ before leaving the receptor, then activates its target

GDP; GTP

7-TMS/G-Protein Coupled Receptors

- The alpha (a) subunit then ________ GTP to form GDP again, allowing the subunit to bind to the receptor and start over again

hydrolyzes

7-TMS G-Protein Coupled Receptors

- Some receptors are coupled to G proteins with a _________ alpha subunit (Gs proteins)

stimulating

7-TMS G-Protein Coupled Receptors

- Some receptors are coupled to G proteins with an _________ alpha subunit (Gi proteins)

inhibitory

7-TMS G-Protein Coupled Receptors

- Each active receptor protein can activate several G proteins, and each target that a G protein activates can….

produce several copies of signaling molecules

7-TMS G-Protein Coupled Receptor Targets

- Targets of G-Protein Coupled Receptors - Adenylyl cyclase ->

produces cAMP

7-TMS G-Protein Coupled Receptor Targets

- Targets of G-Protein Coupled Receptors

- Guanylyl Cyclase ->

produces cGMP

7-TMS G-Protein Coupled Receptor Targets

- Targets of G-Protein Coupled Receptors

- Phospholipase C ->

causes inositol phosphate and dicylglycerol formation

7-TMS G-Protein Coupled Receptor Targets

- Targets of G-Protein Coupled Receptors

- Ion channels ->

calcium and phosphate channels

7-TMS G-Protein Coupled Receptor Targets

- Targets of G-Protein Coupled Receptors

- Mitogen-activated protein (MAP) kinases ->

controls cell division = critical in cancer

• Receptor Tyrosine Kinases (RTKs)

• - Class of enzyme linked cell surface receptors

• - Binding results in activation of their intrinsic tyrosine kinase activity

• - Leads to phosphorylation of tyrosine residues on the receptor and downstream signaling proteins

Enzyme-Linked Receptors

Type of Enzyme-Linked Receptors that possess intrinsic tyrosine kinase activity and are activated by growth factors

Tyrosine Kinases (RTKs)

Type of Enzyme-Linked Receptors that don't have intrinsic kinase activity but recruit and activate associated intracellular tyrosine kinases, like the Janus Kinase (JAK)

Tyrosine-Kinase-Associated Receptors

Type of Enzyme-Linked Receptors that activate by phosphorylating serine or threonine residues on intracellular proteins

Receptor Serine/Threonine Kinases

Type of Enzyme-Linked Receptors that catalyze the production of the cyclic GMP, which acts as a second messenger

Receptor Guanylyl Cyclases

Type of Enzyme-Linked Receptors that inhibit signaling by removing phosphate groups from phosphorylated proteins

Receptor Tyrosine Phosphatases

What are the two major classes of enzyme linked receptors?

Tyrosine Kinase and Cytokine Receptors

What recognizes and binds specific growth factors, hormones, or cytokines?

Extracellular Ligand-Binding Domain

What anchors the receptor in the plasma membrane?

Single Transmembrane a-Helix

What catalyzes ATP-dependent phosphorylation of tyrosine residues?

Intracellular Tyrosine Kinase Domain

Class of receptors located in the cytoplasm or nucleus that bind lipid soluble hormones (e.g., cortisol, estrogen, and testosterone)

Intracellular Receptors

• Acts as ligand-activated transcription factors, regulating gene expression - Direct modulation of gene expression - Regulate gene expression by binding DNA at hormone response elements (HREs)

Primary mechanism of intracellular receptors

Ligand-Binding Domain, DNA-Binding Domain (DBD), and Transactivation Domain make up….

the structure of intracellular receptors: Steroid Hormone Receptors (SHRs)

Part of the intracellular receptors (SHRs) that recognize and bind the hormone

Ligand-Binding Domain

Part of the intracellular receptors (SHRs) that contain zinc finger motifs for binding to hormone response elements (HREs) on DNA

DNA-binding Domain (DBD)

Part of the intracellular receptors (SHRs) that interacts with co-activators or co-repressors to regulate transcription

Transactivation Domain