L13 Flashcards
what are the 3 stages of signal transduction
an extracellular signal molecule activates a membrane receptor (stage 1)
that in turn alters intracellular molecules to be transduced via a certain pathway (stage 2)
to activate a cellular response (stage 3)”
what is the first messenger
The extracellular signal molecule
what is second messenger system
a system formed by intracellular molecules
what are transducers
membrane proteins in between first and second messenger system that convert the message of extracellular signals into intracellular messenger molecules that trigger a response
what are the Types of response in signal transduction
altered ion transport
altered metabolism
altered gene expression
altered cell shape or movement
altered cell growth and division
what chemicals can serve as extracellular signalling molecules? give examples
Amines (e.g. epinephrine, adrenaline)
Peptides & Proteins (e.g. angiotensin II, insulin)
Steroids (e.g. hormones)
Other small molecules (e.g. amino acids, ions, gases)
what are the differences between cell surface and intracellular receptors interaction
molecules that bind trans membrane receptors can’t cross the plasma membrane
nuclear receptors are hydrophobic and mostly act as transcription factors and give a slow response
Membrane receptors are hydrophilic and signaling molecules activate a wide variety of intracellular “signal transduction” pathways (e.g. ion-channels, G proteins coupled receptors and catalytic receptor), including gene regulation. they give a fast response
what are the types of receptors
Ligand-gated ion channels
G-protein coupled receptors
Enzyme-linked receptors
Nuclear receptors
what receptors give rise to the fastest response
Ligand-gated ion channels
then G protein channels
what are Ionotropic receptors
receptors that are ion channels
give examples of Ionotropic receptors
Nicotinic acetylcholine receptor
The gamma-amino buytyric acid (gaba)A receptor
what are the features of Nicotinic acetylcholine receptor
Ligand gated ion channel that mediates effects of acetylcholine (ACh) on muscle etc
Binding of acetylcholine between alpha and delta subunits opens a channel and allows Na+ entry
Binds nicotin
Electrical event (inward Na+ current) triggers response
Calcium may also enter from this channel
what are the features of The gamma-amino buytyric acid (gaba)A receptor
selective for Cl- ions
Naturally activated by g-\amino butyric acid – CNS neurotransmitter
Inhibitory receptor
Very important role in CNS
Activated by benzodiazepines
Also by alcohol and anesthetics
what are Benzodiazepines
sedative drugs that activate The g-amino buytyric acid (gaba)A receptor
what are Metabotropic receptors
receptors that are not ion channels but cause the opening of ion channels. they are indirectly linked with ion channels on the plasma membrane through signal transduction pathways, generally G proteins mediated
give examples of Metabotropic receptors
Muscarininc
Gaba B
what are the features of Muscarinic receptors
activated by ACh
More sensitive to muscarine than nicotine
what are the features of Gaba B receptors
activates a Potassium channel
More sensitive to muscarine than nicotine
what are the features of G protein coupled receptors
Receptors that activate G proteins all have 7 transmembrane domains
At least 800 genes encode G protein coupled receptors
what are the polypeptide chains of g proteins
alpha, beta and gamma
how many subunits are there for each G protein polypeptide
16 alpha subunits,
5 beta
11 gamma
what 2 G protein subunits bind tightly, effectively forming a single subunit
beta and gamma
what subunit has a guanine nucleotide binding site that binds GTP or GDP
alpha
compare alpha GDP and alpha GTP
alpha-GDP has high affinity for beta gamma (resting conditions)
alpha-GTP has low affinity for beta gamma
which subunit can hydrolyze GTP
alpha
whare is the G protein complex located
inside plasma membrane
what are the steps in the G protein cycle
e.g.
Adrenaline binding to beta-adrenoceptor
Allows b-adrenoceptor / G protein interaction
GDP on alpha subunit is exchanged for GTP
Allows alpha subunit liberation
Free a subunit activates adenylyl cyclase AC
activated AC generates cAMP by hydrolising ATP
Unbinding of adrenaline /
GTP hydrolysis (1 GTP hydrolysed each time ‘round cycle)
what does cAMP do
activate Protein Kinase A (PKA)
what are the features of PKA
PKA is a tetrameric protein with two types of polypeptide chains Catalytic (C) and regulatory (R)
Inactive PKA - subunits bound together and R subunit suppresses activity of C subunit
R subunits have 2 binding sites for cAMP
cAMP binding allows the subunits to dissociate
Catalytic subunits become active….phosphorylate other proteins.
PKA catalyzes transfer of ATP to specific serine or threonine residues on substrate proteins
what physiological responses are mediated by cAMP / PKA
Kidney collecting duct – activated by vasopressin and stimulates water retention
Vascular smooth muscle and Cardiac muscle – activated by adrenaline and promotes relaxation/increase heart rate
Colonic epithelium – activated by various factors and promotes fluid / electrolyte secretion
Pancreas –activated by glucagone and promotes release of glucose in the blood
how can the G protein cycle end
Removal/inactivation of signal
Removal/inactivation of receptor
Inactivation of activated signalling proteins
- GTP hydrolysis
- dephosphorylation
Degradation/removal of second messengers
hew is the removal of second messengers achieved
cAMP is hydrolysed by phosphodiesterase (PDE)
When hormone is removed, PDE rapidly clear cAMP from the cell
Unbinding of cAMP from R subunit increases affinity for C subunit
Protein reassembles into tetramer and are inactivated
PDEs are inhibited by caffeine. Interfering with a “switch off” mechanism prolongs the time on and indeed prolongs a cellular response
how is desensitization of receptor achieved
(1) Protein phosphorylation
leads to cellular response
(e.g. Glucose release)
(2) PKA phosphorylates beta-ARK and increases activity
(3) beta-ARK phosphorylates b-adrenoceptor and reduces affinity for adrenaline
(4) Reduced affinity leads to reduced cellular response despite sustained stimulation
what protein does Dephosphorylation
Protein phosphatases
what molecule is never part of the G protein signaling
GABAA
