Physiology Receptors

Receptor Definition

A specific macromolecule or binding site located on or within a cell that interacts with a drug, endogenous ligand(such as a hormone or neurotransmitter), or other signaling molecule to initiate a physiological or biochemical response.

Ligand

A signaling molecule such as a neurotransmitter or drug

Receptor

Protein embedded in the cell membrane.

Signal Transduction (broad)

Once the ligand binds, the receptor changes shape and starts a chain of events inside the cell.

4 Signal Changes Pathway

External signal, receptor, intracellular signal, cellular response

Drug Action Pathway

Drug Administration, Distribution to Target Tissue, Binding to Molecular Target, Biochemical Change, Physiological Response

4 Receptor Locations

Plasma membrane, cytoplasm, nucleus, free in blood

5 Functions of the receptor

Regulate a physiological function, the flux of ions, a biochemical function, the expression of mRNA, blood clotting

3 Receptor Activators

Neurotransmitters, Peptides, Hormones

3 Receptor Physical Characteristics (General)

Protein based, Purely nucleic acid (DNA), Quaternary Structure (multiple subunits?)

3 Plasma Membrane Domains

Extracellular Domain, Transmembrane Domain, Intracellular Domain

Extracellular Domain

Binds ligands

Transmembrane Domain

Hydrophobic helices anchor the receptor in the lipid bilayer

Intracellular Domain

Initiates downstream signaling

Downstream Signaling

Activation of enzymes, second messengers, or signaling cascades

Plasma membrane receptors can be composed of _

Multiple protein subunits

Homodimers

Two identical subunits

Heterodimers

two different subunits

Heteropentameric ion channels

Includes 5 different or homologous subunits, GABA-A receptors, Nicotinic Acetylcholine Receptors

Receptor families can differ in _

tissue distribution, ligand preference, function

6 General Characteristics of Receptor Activation

Ligand Binding, Conformational Change, Signal Transduction, Intracellular Activation, Amplification, Cellular Response

Ligand Binding

Involves receptor recognition

Conformational Change

Binding induces a structural rearrangement in the receptor

Signal Transduction (Receptor Activation)

Transmitted across the plasma membrane through the transmembrane domain, Activating some biological activity

Intracellular Activation

Intracellular domain initiates signaling cascades (e.g. phosphorylation, second messengers)

Amplification

A single ligand-receptor interaction can activate multiple intracellular pathways

Cellular Response

The cell responds with changes in gene expression,metabolism, or functional behavior

Desensitization or tachyphylaxis

Process by which a cell's response to a signaling molecule, or agonist, decreases following repeated or prolonged exposure. Crucial negative feedback mechanism that prevents overstimulation

Receptor desensitization is caused by _

Modification of receptor by other proteins, Receptor internalization, Exhaustion of signaling mediators

Molecular Size Impact on Receptor Binding

Fit into receptor binding pocket. Permeability (smaller = easier membrane passage). Selectivity (larger = more specific interactions)

Molecular Shape Impact on Receptor Binding

Lock-and-Key fit with receptor. Induced fit = conformational change. Stereochemistry = enantiomer specificity

Structure: Ligand-Gated Ion Channels (what class?)

Class: nicotinic ACh receptor (what structure?)

Structure: GPCRs (what class?)

Class: beta-adrenergic receptor (what structure?)

Structure: Enzyme-linked receptors (what class?)

Class: tyrosine-kinase receptors (what structure?)

Structure: Intracellular receptors (what class?)

Class: Steroid hormone receptors (what structure?)

LGIC definition

Ligand-Gated Ion Channel is a transmembrane protein that forms an ion-conducting pore in the cell membrane

What LGIC do?

It opens in response to the binding of a specific chemical signal (ligand), such as a neurotransmitter

LGIC Activation

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

LGIC Function

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

LGIC Speed

Mediates fast synaptic transmission—changes in membrane potential occur within milliseconds

LGIC Specificity

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

GABAA Receptor

Cl- channel activated by Y-aminobutyric acid

NMDAR

Ca2+/Na+ channel activated by glutamate and glycine

GPCRs

Diverse family of cell surface receptors

Relay signals from the outside to the inside of a cell

Vast array of physiologic processes

β-Adrenergic receptors (broad)

a subclass of G protein-coupled receptors (GPCRs)

Respond to the catecholamines epinephrine and norepinephrine

Mediate a variety of physiological processes, Particularly in the cardiovascular and respiratory systems

β-Adrenergic receptors (structure e.g. extracellular and intracellular domain, subtypes)

Single polypeptide chain with 7 transmembrane α-helices

Extracellular domain – contains the ligand-binding site.

Intracellular domain – couples to heterotrimeric G proteins.

β₁, β₂, β₃

β₁ (where and what it do)

Predominantly in the heart;
increases heart rate and
contractility.

β₂

In smooth muscle
(bronchi, vasculature); causes
relaxation.

β₃

In adipose tissue;
stimulates lipolysis.

Steps of 7-TMS G-Protein Coupled Receptors

Receptor is activated -> α and βγ subunits dissociate, each activating a separate target
• The α subunit swaps GDP for GTP before leaving the receptor, then activates its target
• The α subunit then hydrolizes GTP to form GDP again, allowing the subunit to bind to the receptor and start over again

Gs proteins

Some receptors are coupled to G proteins with a stimulating α subunit

Gi proteins

Some receptors are coupled to G proteins with an inhibitory α subunit

Gq protein pathway

A G-protein-coupled receptor signaling cascade that activates phospholipase C to increase intracellular calcium and protein kinase C.

5 Targets of G protein-Coupled Receptors and What They Do

• Adenylyl cyclase – produces cAMP
• Guanylyl cyclase – produces cGMP
• Phospholipase C – causes inositol phosphate and diacylglycerol formation
• Ion channels – calcium and potassium channels
• Mitogen-activated protein (MAP) kinases – controls cell division – critical in cancer

Endogenous Activators (7)

Norepi & Epinephrine, Serotonin, Acetylcholine, Histamine, Enkephalins, Vasopressin (ADH)

7-TMS GCPR Receptors examples

• Adrenergic receptors (α and β receptors)
• Serotonergic receptors (5-HT receptors)
• Muscarinic cholinergic receptors (M1 , M2 , M3 , M4 , M5 )
• Histamine receptors (H 1 and H 2 receptors)
• Opioid receptors
• Vasopressin receptors
• Taste receptors
• Olfactory receptors
• Leukotriene receptors

2 Major Classes of Enzyme-Linked Receptors

Tyrosine Kinase and Cytokine

Tyrosine Kinases (RTK)

Binding results in activation of their intrinsic tyrosine kinase
activity. Activated by growth factors.
Leads to phosphorylation of tyrosine residues on the receptor and downstream signaling proteins

Tyrosine Kinase-Associated Receptors

Don't have intrinsic kinase activity but recruit and activate
associated intracellular tyrosine kinases, like the Janus kinase (JAK)

Receptor Serine/Threonine Kinases

Activate by phosphorylating serine or threonine residues on
intracellular proteins

Receptor Guanylyl Cyclases

Catalyze the production of cyclic GMP, which acts as a second
messenger

Receptor Tyrosine Phosphatases

Inhibit signaling by removing phosphate groups from phosphorylated
proteins

Structure of Enzyme-Linked Receptors

-Extracellular ligand-binding domain
• Recognizes and binds specific growth factors, hormones, or
cytokines.
– Single transmembrane α-helix
• Anchors the receptor in the plasma membrane.
– Intracellular tyrosine kinase domain
• Catalyzes ATP-dependent phosphorylation of tyrosine residues

What are Intracellular Receptors (SRH)?

ex. Corticosteroids, mineralocorticoids, sex steroids, vitamin D, thyroid hormone

They are receptors located in the cytoplasm or nucleus that bind lipid-soluble hormones (e.g., cortisol, estrogen, testosterone).

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

Structure of Intracellular Receptors

– Ligand-binding domain – Recognizes and binds the hormone.
– DNA-binding domain (DBD) –Contains zinc finger motifs for binding to hormone response elements (HREs) on DNA.
– Transactivation domain – Interacts with co-activators or co-repressors to regulate transcription.