Commissaris Ch 12 ligands and receptors

_______________ is the process by which cells release, transmit, receive, and respond to info from their environment

cell signaling

what is the foundation of pharmacology

physiology

= drugs work as ligands at receptors involved in already existing processes

what are the 3 main players involved in intercellular signaling

1. signaling cell= makes the ligand

2. ligand= transmits info from signaling cell to recipient cell

3. recipient cell= receives ligand

endogenous ligand

any substance, produced within the body, that selectively binds to the type of receptor that is under study to initiate some change

using insulin as an example, identify the 3 main players of cell signaling

signaling cell= pancreatic beta cells (release insulin)

ligand= insulin

recipient cell= insulin receptors in muscle

explain the steps of intercellular signaling

1. synthesis and/or storage of ligand

2. release of ligand (via stimulus) and transport to target

3. formation of ligand-receptor complex

4. receptor-based change in cell function

5. removal of ligand

what is the difference between substrate-enzyme and drug-receptor

sub/enz= substrate is CHANGED to form new PRODUCT

drug/receptor= drug LEAVES receptor while EFFECT happens (drug is not changed!)

what are the 4 ways endogenous ligands can be classified

1. chemistry/structure

=charged vs non-charged; small organic vs protein

2. receptor with which it interacts

=extracellular or intracellular?

3. anatomy and phys

=NT (local), hormones (distant), steroids (intracellular)

4. signal transduction mechanism

CRAS

what determines whether a ligand acts extracellularly or intracellularly

whether it can penetrate membrane

hydrophilic ligand= cell surface

hydrophobic ligand= intracellular

T/F: a polar ligand will work on intracellular receptors

false!

-polar ligands are hydrophilic and work on the cell surface.

-nonpolar ligands are hydrophobic and can get pass the bilayer

exocrine vs endocrine glands

Exocrine glands secrete their products into ducts, NOT BLOOD STREAM (ex: sweat, salivary)

Endocrine glands secrete hormones directly into the bloodstream

hormones

chemical messengers that are manufactured by the endocrine glands, travel through the bloodstream, and affect other tissues (ex: insulin)

3 types of hormones based on chemistry

1. steroids

2. amino acid derivatives

3. peptides/proteins

intracellular hormones are hydro____ and _________ the cell membrane

hydrophobic; can cross cell membrane (or can be transported into cell)

what do most intracellular hormones modulate

gene expression in target cells

extracellular hormones are hydro____ and _________ the cell membrane

hydrophilic (charged); cannot cross cell membrane

how is endocrine hormone signaling terminated

elimination of hormones from blood (via liver metabolism)

3 features of local signaling of endogenous ligands

1. no bloodstream transport needed

2. effects are near the source of the signal

3. short-term effects

(ex: neurotransmitters)

3 types of local signaling

1. paracrine= cell A to cell B

2. autocrine= cell A to cell A

3. juxtacrine= direct contact btwn cell A and cell B

what is the most prevalent form of local signaling

paracrine (cell A to cell B through fluid)

T/F: exocrine glands play a small part in intercellular signaling

false. they are not a part of cell signaling. they immediately release product into ducts

3 ways you get specificity of ligand-receptor interactions

1. chemical specificity of ligand-receptor

2. anatomical specificity via receptor location

3. limited distribution of ligand in body

If TSH goes everywhere in the body when it is released, why does it only act on the thyroid?

1. chemical specificity= only binds to thyroid receptors

2. anatomical specificity= receptor is only found in thyroid gland tissue

even though NE can bind to many tissues and many receptors, what allows it to only act on one specific target?

1. limited distribution

= the neuron it is released from is close to target cell; little opportunity to diffuse to affect other cells

stereoselective

describes receptors; they prefer one stereoisomer over another of a ligand

ex: levothyroxine: levo fits better than dextro

stereo complementarity

ligand must be the correct stereoisomer to fit stereoselective binding site of receptor

recognition

ligand binds to receptor (usually reversible)

noncatalytic vs catalytic receptors

non= majority

-ligand is agonist/antagonist on RECEPTOR; released UNCHANGED

catalytic= minority

-works on enzymes

- ligand can be ENZYME inhibitor, or SUBSTRATE for enzyme (changed)

ex: lisinopril= ACE inhibitor

what are receptor subtypes

groups of receptors with similar binding domains but different signal transduction mechs

= so same ligand, different effect

ex: NE -> alpha 1, alpha 2, beta 1, beta 2

T/F: if 2 receptors are both noradrenergic receptors, they have identical signal cascades

false. they may be different NE subtypes and have different response

ex: alpha 1, alpha 2, beta 1, beta 2

what are some differences between drugs that bind to only one receptor subtype and those that bind to many subtypes

one subtype: drug is selective

many subtypes: may cause unwanted side effects

__________________ refers to the process by which an extracellular ligand-receptor interaction causes an intracellular change

signal transduction

first vs second messengers

first= original ligand that binds to receptor

second= short lived compound within cell that transmits signal

examples of second messengers

cAMP, calcium ions, IP3, DAG

old way vs new way of receptor classification

1. old way= receptor classified by what LIGAND it binds

ex: NE receptor

2. new way= based on location and type of SIGNAL TRANSDUCTION pathway

ex: GPCR

3 types of extracellular cell-surface receptors

1. ion channel

2. GPCR

3. enzymatic

** ligands cannot cross membrane (hydrophilic, polar)

2 types of intracellular receptors

1. transcription regulation (nuclear)

2. intracellular enzymes

**ligands cross cell membrane (hydrophobic)

common ions that pass through ion channels

Na, K, Ca, Cl

T/F: ions can pass through the lipid membrane and act on intracellular receptors

false. ions are charged, therefore they cannot pass the membrane and require ion channels

ligand vs voltage gated ion channels

1. Ligand

- ligand binds to ion channel receptor= conformational change

- change opens ion channel and allows ion movement

2. Voltage

-membrane voltage reaches threshold= triggers opening of channel

-occurs in excitable cells (neuron, cardiac)

the GABA receptor is an example of what kind of receptor? how does it work?

Ligand gated ion channel receptor

1. GABA binds to receptor on Cl- ion channel outside of cell

2. conformational change= Cl- ions enter cell

3. negative Cl ions make cell hyperpolarized (more negative)= INHIBITORY EFFECT

T/F: GABA binds to its receptor on the Cl ion channel, allowing Cl to enter and an action potential to form

false. Cl- is negative and makes the cell hyperpolarized, meaning it is less likely for an AP to form

= GABA is inhibitory

T/F: when a ligand binds to its voltage gated ion channel, the ion channel opens

false. voltage-gated ion channels do not have ligand receptors

examples of excitable cells that have voltage gated ion channels

Neural and cardiac

= Na+ rushes in

which extracellular cell surface receptors are most often targeted by drugs

GPCRs (more than half of drugs on market)

which receptor is a single peptide with 7 transmembrane regions

GPCR

what are the 3 subunits of the G protein in GPCRs

1. alpha= GTP ->leaves and interacts with adenylate cyclase

2. beta

3. gamma

Gs, Gi= linked to ______

Gq= linked to ______

Gs, Gi= linked to _adenylate cyclase__

Gq= linked to __phospholipase C_

the beta 1 adrenergic receptor is a classic example of a ________

GPCR; increase in cAMP

describe what happens to the GPCR when NE binds

1. Ne binds-> GDP is exchanged for GTP on alpha subunit

2. GTP-alpha dissociates and interacts with adenylate cyclase

3. adenylate cyclase: ATP-> cAMP

3. cAMP (2nd messenger) produces intracellular response

4. GTP-> GDP, alpha migrates back

adenylate cyclase

Activated by a GTP-alpha. Converts ATP to cAMP

T/F: enzymatic receptors have 7 membrane spanning regions

false. GPCRS have 7, while enzymatic receptors have 1

which receptors are often found in pairs (dimers)

enzymatic

what happens when a ligand binds to an enzymatic receptor

triggers enzymatic activity inside cell

**the ligand is NOT the substrate for the enzyme

**enzyme can be continuous or non-continuous with receptor

the protein kinase receptor family is an example of what kind of receptor

enzymatic receptor

transcription regulation receptors are also known as __________ and act to ______-

nuclear receptors; ligand acts in nucleus to initiate transcription of RNA from DNA

2 subcategories of nuclear receptors

1. steroid (corticosteroids, sex steroids..)

2. non-steroid (thyroid, vitamin D, retinoic acid)

describe what happens in intracellular enzymes

ligand binds to enzyme inside cell and changes into product

OR ligand inhibits enzyme (suicide substrate)

3 factors influencing ligand-receptor interactions

1. ligand concentration (more ligand= more binding)

2. receptor density

3. allosteric modulation

upregulation vs downregulation

1. upregulation: increase in number of receptors

- observed in absence of ligand

ex: increased dopamine receptors in Parkinsons

2. downregulation: decrease in number of receptors

-observed in excess of ligand

ex: chronic beta-agonist treatment (inhalers)

allosteric modulation

2 binding sites: one for ligand and one for modulator (allosteric site)

modulator alters the shape of the ligand binding site and, therefore, the binding characteristics of that site

describe the effect of benzodiazepines as allosteric modulators

BDZs bind to allosteric receptors, causing GABA to bind better to its ligand receptor and therefore increasing the amount of Cl ions moving in