Foundations Final Sprowls-Drug Receptors 2

most transmembrane signaling accomplished through mechanisms adapted from distinct __ families (like receptors on surface/within cells, enzymes, etc)

protein

second messengers= these are __-___ intracellular chemical mediators that amplify signal

non-protein

5 basic mechanisms for transmembrane signaling:

1) intracellular receptors for __ soluble agents

lipid

Some ligands are able to cross the ___ membrane to act on intracellular receptors for lipid-soluble agents (like steroids, vitamin D, etc)

plasma

activation of these intracellular receptors for lipid-soluble agents stimulates the ___ of genes by binding to specific DNA sequences (called response elements) near a gene whose expression will be regulated

transcription

when these receptors for lipid-soluble agents are ___ into their functional conformations, the DNA-binding/transcription-activating domains will initiate transcription of target genes

folded

using hormones that regulate gene expression consequence 1= there is a ___ ___ for their effects

lag period

using hormones that regulate gene expression consequence 2= effects of agents can ___ for hours to days after concentration has been reduced to 0 due to slow __ of proteins/enzymes meaning that the drug effects (either beneficial or toxic) will decrease slowly after hormone therapy stopped

persist, turnover

5 basic mechanisms for transmembrane signaling:

1) intracellular receptors for lipid soluble agents

2) ___ regulated transmembrane enzymes (+RTKs)

ligand

ligand-regulated transmembrane enzymes mediate first steps in signaling by ___ hormones (means hormones can't cross cell membrane)

trophic

Ligand-regulated transmembrane enzymes consist of:

-an __ domain that binds to the hormone

-a ___ enzyme domain

extracellular, cytoplasmic

Ligand-regulated transmembrane enzymes consist of

an extracellular domain that binds to the hormone and a cytoplasmic enzyme domain, which are connected by a ___ segment in lipid bilayer

hydrophobic

when hormone binds to extracellular domain, Ligand-regulated transmembrane enzymes are activated as 2 receptor molecules bind to one another (called ___)

dimerization

___ (Receptor Tyrosine Kinases) are a type of ligand-regulated transmembrane protein.

RTKs

when hormone (example-EGFR) binds to RTK:

1) the 2 receptor molecules will dimerize

2) this will activate tyrosine kinase activity and result in __-___ of receptors

3) now the receptors can ___ other proteins to modulate biochemical processes

cross-phosphorylation, phoshorylate

RTKs (type of ligand-regulated transmembrane protein) are common targets for ___ disorders where there is excessive EGF (epidermal growth factor)

neoplastic

there are drugs that treat cancer by:

-some drugs bind to and inhibit __ domain

-some drugs inhibit ___ activity in cytoplasm

extracellular, kinase

The intensity and duration of ligand-regulated transmembrane enzymes are limited by ____ — a process in which ligand-bound receptors are internalized via endocytosis and degraded. If this degradation exceeds the rate of new receptor synthesis, the cell becomes less sensitive to the ligand.

downregulation

endocytosis typically associated with ___

downregulation

endocytosis typically associated with downregulation, but can sometimes be a good thing, like when receptors for nerve growth factors are internalized, but remain ____ and control genes critical for cell survival

active

5 basic mechanisms for transmembrane signaling:

1) intracellular receptors for lipid soluble agents

2) ligand regulated transmembrane enzymes (+RTKs)

3) ___ receptors

cytokine

Cytokine receptors respond to heterogeneous group of ___ ligands (like growth hormone, erythropoietin, interferons, etc)

peptide

cytokine receptor mechanism closely resembles RTKs, but the protein tyrosine kinase activity is NOT ____ to the receptor protein

intrinsic

once bound by ligand, cytokine receptors ___

dimerize

after cytokine receptors bound by ligand and dimerize, the mobile protein tyrosine kinase molecules, for the __-___ (JAK) family proteins will noncovalently bind to intracellular domain

janus kinase

once JAK proteins bound, they will ____ the receptor's intracellular domain

phosphorylate

once JAK proteins bound, they will phosphorylate the receptor's intracellular domain, allowing for the binding of signal transducers and activators of transcription (abbreviated ____)

STATs

bound STATs are then ___ by JAKs

phosphorylated

after STATs bind and are phosphorylated, they ___ (attach to one another's tyrosine phosphates), then dissociate from receptor, then travel to nucleus to regulate genes

dimerize

5 basic mechanisms for transmembrane signaling:

1) intracellular receptors for lipid soluble agents

2) ligand regulated transmembrane enzymes (+RTKs)

3) cytokine receptors

4) __ channels

ion

many of most useful therapeutics for ion channels often __ or ___ the actions of natural agonists (like GABA, seratonin, etc)

mimic, block

when ion channel opens, the __ ___ of ion is increased, which alters electrical potential of membrane

transmembrane conductance

drugs that regulate neurotransmitter activity often bind to extracellular ligand __ ___, or to surfaces on membrane portion of receptor, or within pore

binding pockets

time elapsed between ligand-gated ion channel agonist activation and cellular response is very rapid or slow?

rapid

a subset of ion channels, the ___-gated ion channels, do NOT bind neurotransmitters

voltage

voltage-gated ion channels are directly controlled by __ ___

membrane potential

drugs that target voltage-gated ion channels commonly bind to site different than charged amino acids that constitutes the "__ __" domain of the protein

voltage sensor

not all drugs that act on voltage-gated ion channels inhibit or activate, some correct ___ in disease states like in cystic fibrosis

malfunction

5 basic mechanisms for transmembrane signaling:

1) intracellular receptors for lipid soluble agents

2) ligand regulated transmembrane enzymes (+RTKs)

3) cytokine receptors

4) ion channels

5) ___ ___ & __ ___

G proteins, second messengers

extracellular ligands that act by G proteins and second messengers have a ___ step process for activation

3

Process for G proteins/second messenger activation:

1) binding of __ to cell-surface receptor

ligand

Process for G proteins/second messenger activation:

1) binding of ligand to cell-surface receptor

2) receptor activates ___ protein (GTP binding protein)

G

Process for G proteins/second messenger activation:

1) binding of ligand to cell-surface receptor

2) receptor activates G protein (GTP binding protein)

3) G protein changes activity of __ element, which then changes intracellular concentration of a ___ messenger

effector, second

G proteins will rapidly activate their downstream effects when bound by __

GTP

G proteins will be inactivated by ___ GTP

hydrolyzing

Rate of GTP hydrolysis by G protein is major determinant of __ and __ of downstream response

duration, amount

the same ligand may bind to a receptor and activate a different G protein depending on the __ ___

cellular context

receptor signaling through G proteins is called what?

g protein coupled receptors

g protein coupled receptors also called __ receptors because polypeptide chain snaked across cellular plasma membrane 7 times

serpentine

many GPCRs able to act as ___, meaning they are singular receptors capable of transducing an extracellular signal

monomers

many GPCRs act as monomers, others require assembly of __ or ___ for functional activity

homodimers, heterodimers

GPCR signal transduction:

1) agonist will bind to receptor to stabalize conformation state in which cytoplasmic ends of transmembrane helices open by ___ nanometer, which opens a cavity where G protein can __

1, dock

GPCR signal transduction:

2) after G protein docks/binds, its ___ for nuclotides is reduced, which allows dissociation and binding of __

affinity, GTP

GPCR signal transduction:

3) after G protein binds to GTP, it will dissociate from receptor and engage downstream ___

effects

Binding of agonist to GPCR acts as the molecular switch, exchanging GDP for GTP on G protein, which ___ the G protein!

activates

G protein mediated responses to agonists or drugs often attenuate with __

time

G protein mediated responses to agonists or drugs often attenuate with time, which means response will diminish, and ____ will occur in continued presence of agonist

desensitization

the desensitization period phenomenon is rapidly ___

reversible

the desensitization period phenomenon is rapidly reversible, meaning if enough time has passed following initial agonist binding, a __ exposure to agonist produces similar response

second

in some cases, the desensitization period is much more ___, resulting in longer suppression of cell/tissue response

persistant

the second messenger cyclic adenosine monophosphate (cAMP) is produced by __ _

adenylyl cyclase

cAMP acts mainly by stimulating cAMP-dependent __ __

protein kinases

cAMP-dependent protein kinases composition:

-two ___ (C) chains

-___ of cAMP-regulatory (R) domains

catalyctic, dimer

when R dimer is bound by cAMP, active C chains are ___ and interact with ___ proteins, using ATP to phosphorylate their targets

released, substrate

termination of cAMP action:

1) the phosphorylated enzymes will be reverse by group of __

phosphatases

termination of cAMP action:

2) cAMP will be degraded to 5-AMP by multiple cyclic nucleotide ___

phosphodiesterase

GPCRs that activate phospholipase C (PLC) will in turn regulate the secondary messengers of ___ and intracellular ___

phosphoinositides, calcium

PLC splits ___

PIP2

PLC splits PIP2 into __ and __

DAG, IP3

DAG is confined to plasma membrane, but activates another enzyme called protein kinase C (___)

PKC

IP3 diffuses through cytoplasm to induce release of ____

calcium

calcium will bind to ____, which will activate calcium-dependent protein kinases

calmodulin

termination of phsophoinositides/calcium action:

-____ of IP3

-_____ of DAG

-removal of Ca2+ from inside cell by Ca2+ efflux pumps

dephosphorylation, phosphorylation

the second messenger cyclic guanosine monophosphate (cGMP) is produced by __ _

guanylyl cyclase

cGMP pathway very similar to cAMP-- the cGMP dependent protein kinases go on to ___ their substrates

phosphorylate

termination of cGMP action:

-___ degredation of cGMP

-_____ of substrates of specific kinases

enzymatic, dephosphorylation