Exam 3

Pharmacology

Interaction of chemicals with biological systems, focusing on mechanism of action, therapeutic effects, and potential side effects

Pharmacodynamics

What the drug does to the body, how drug interacts with cellular targets and how these interactions produce biological responses

Pharmacokinetics

What the body does to the drug, absorption, distribution, metabolism, and excretion

Receptor

A protein molecule found on surface or within cells, binds to a specific signaling molecule to initiate a cellular response

Ligand

Any chemical that will bind to a receptor

Agonist

A ligand that activates a receptor and generate a biological response, specific ligands are needed for a receptor, promotes/enhances cell signaling

Antagonist

A chemical that prevents or reduces a biological response, may act at a receptor or by other mechanisms, brings response to 0

Drug

Chemical that alters physiologic function of cells and tissues through a chemical reaction, prevents/treats/ gives symptomatic relief of disease, scientific tool to study cell/tissue function

Neurotransmitters

Chemical messengers released by neurons that transmit signals across a synapse to target cells, fast acting

What are the examples of neurotransmitters

Norepinephrine, acetylcholine, GABA, and 5-HT

Hormones

Chemical messengers secreted by glands into the bloodstream, travel to target tissues or organs to regulate long-term processes, slower acting

What are examples of hormones?

Aldosterone, estrogen, thyroid hormone

What are the types of agonists

Full, partial, inverse, allosteric, biased

What are the types of antagonists?

Physiologic, chemical, competitive, noncompetitive, allosteric

What is the MW of a ligand?

100-1000g/mole

Lock and key hypothesis

Earliest model, ligands have a complementary shape to the receptor for binding to occur

How do functional groups affect ligand- receptor binding?

They allow a chemical bond to form between the drug ad the receptors binding pocket

Function of a receptor

Site of neurohormone and drug action, regulate physiological systems, regulate biochemical processes

Where can receptors be located?

Cell membrane, cytoplasm, and nucleus

Transduction

Transmitting information into and throughout the cell

What are the types of membrane receptors?

G-protein coupled receptor, ligand gated ion channels, enzymatic, and cytokine

What are the types of intracellular receptors?

Nuclear and cytoplasmic

Ligand-binding domain

Binds specifically to the ligand

Transmembrane domain

Hydrophobic, spans the lipid bilayer, anchors the receptor to the membrane

Effector/ signaling domain

Interacts with signaling proteins

Affinity

Strength of the interaction between a receptor and drug, Kd, higher Kd=lower affinity

Selectivity

Describes a drugs preference/ affinity for one receptor/target over another

Specificity

A precise molecular complementarity between the signal and receptor molecules, mediated by noncovalent forces

How can a high dose of a drug affect selectivity or specificity?

It can reduce both

Signal transduction

Cells communicating using extracellular signaling molecules produced and released by signaling cells, the molecules recognized and bind to receptors on the surface of target cells to cause a cellular response through a signal transduction pathway

What are the types of signaling?

Autocrine, paracrine, endocrine

Autocrine

Cell secretes chemical messenger/ hormones that will then activate receptors on the same cell

Paracrine

Cell secretes a chemical messenger/ hormone that will then activate cell-surface receptors on a cell nearby

Endocrine

Cell secretes chemical messenger/ hormone that needs to be transported by the bloodstream to reach a distant target cell

Neuroendocrine cells

Receive neuronal input and release hormones to the bloodstream

Sensitivity

High affinity of signal receptors for their ligands

Kd

Dissociation constant, smaller is more sensitive

Steps of signal transduction

1. Primary messenger is released

2. Receptor binds the primary messenger

3. Intracellular delivery of the cell using second messengers

4. Activation of molecules that directly alter physiological response

   1. Termination of signal

First messenger

Molecules or hormones secreted by cells in one part of the body that influence cells/tissues in another part of the body, agonists

Second messengers

Molecules that transmit signals received at receptors, amplify the signal, usually free to diffuse throughout the cell, one second messenger can be used in multiple pathways

First messenger examples

Hormones, neurotransmitters, pharmacological agonists

Secondary messenger examples

cAMP, cGMP, guanylyl cyclase, DNA binding, ions

Third messenger

Molecules that transmits signal further down a signal transduction pathway

Third messenger example

Calcium

Amplification

An enzyme is activated by a signal receptor and catalyzes the activation of many molecules

Modular

Multiple domains that recognize specific features, all cells to mix and match sets of signaling molecules

Scaffold proteins

Nonenzymatic proteins that bring together enzymes that interact in a cascade

Desensitized

No longer responsive to a signal, happens when a signal is continuously present

Integration

The ability of the system to receive multiple signals and produce a unified response

Divergent

Branched, not linear, occurs when a signal is continuously present

Response localization

Cells confine signaling system components to a structure to regulate processes locally

Inverse agonist

Negative signal response

What are the structural classifications of receptors?

Single pass and multipass

What are the classes of signal transduction receptors?

GPCR, enzyme linked/receptor kinases, ligand-gated ion channels, intracellular receptors

GPCRs

Couple to GTP binding proteins inside the cell to activate them, active G proteins modulate ion channels and enzymes

Enzyme linked receptors

Intrinsic enzymatic activity or are associated with an intracellular enzyme

Ligand/voltage-gated ion channels

Allow specific ions to flow in or out of the cell in response to the binding of a chemical messenger or because of a voltage gradient

Intracellular receptors

Activation of receptors located within a cell results directly in altered gene transcription

G Protein-coupled receptor structure

7 transmembrane helical structures, N-term is outside, C-term is inside

G-protein

Heterotrimeric proteins that bind GTP and GDP using the alpha subunit, active when bound to GTP and inactive when bound to GDP, exchanging GTP for GDP is stimulated by the change in conformation of the receptor

Gs

Activates ADC, increases cAMP levels, alpha subunit is palmitylated

Gi

Inhibits cAMP levels, prevents intracellular Ca2+ from increasing, alpha subunit is myristylated

Alpha subunit

Binds GTP/GDP, has weak GTPase activity to slowly convert GTP to GDP, has a high affinity for the beta/gamma subunits when bound to GDP, disassociates from other subunits when GTP bound

Gamma subunit

Anchors protein in hte membrane

What is the target of G proteins in adrenergic signaling?

ADC

ADC

Catalyzes the conversion of ATP to cAMP and pyrophosphate

Phosphodiesterase