Endocrine Signals
Produced far from the target tissue,reach via the circulatory system
Paracrine Signals
diffusable, short range
Juxtacrine Signals
require physical contact between sending and receiving cells, close range
Autocrine Signals
act on the same cell that produces them
ligand
the messenger that binds to a target receptor
Secondary Messengers
small molecules or ions that relay signals, a cascade of changes
Signal transduction
the ability of a cell to respond to ligand-receptor bingding by altering its behavior or gene expression
When receptors are occupied for too long of a time what happens?
the cell adapts to no longer responding to the ligand
Cells adapting to signals, alterations to the reeptor that lower its affinity for the ligand, a shut off response
desensitization
Agonists
drugs that activate the receptor they are bound to
Antagonists
bind receptors without triggering a change and prevent the naturally occurring messenger from activating the receptor
Once a ligand binds to a receptor it either induces a change in receptor conformation or causes receptors to cluster, what happens next?
a preprogrammed sequence of events inside the cell either through a primary messenger or continuing on to a secondary messenger
What are the pathways of signal integration?
a single receptor can activate multiple pathways or multiple pathways can converge in to onto the same molecules
What are three examples of what can happen in response to a ligand binding?
It activates multiple pathways, a single pathway, or different receptors activate different pathways; one affects the other.
What is signal amplification?
the multiplication of the effect of the signal, by very small quantities that elicit a response from a target cell, resulting in a cascade of events
What are the two basic types of receptors?
ligand-gated channels and plasma membrane receptors
What are the two types of plasma membrane receptors?
Those linked to G-proteins and those linked to protein kinases
What happens when a ligand binds to the G Protein-linked family?
It activates a particular G Protein
What is the structure of G protein-linked receptors?
7 transmembrane alpha helices connected by alternating cytosolic or extracellular loops, these have unique messenger-binding sites
What are heterotrimeric G Proteins?
They have 3 subunits and mediate signal transduction through G protein-linked receptors Galpha Gbeta Gy
What is the purpose of Galpha subunit?
It is the largest subunit of Gaby, it binds to GDP and GTP, when it binds to GTP it detaches from the other subunits which are permanently bound
What is the function of the G protein?
the change in receptor conformation when a ligand binds to the receptor causes the G protein to release its GDP, then Galpha binds to new GTP molecule and leaves the comples, depending on the G protein either the Galpha or Gbetay initiates signal trasnduction
When does G protein become inactive?
The dephosphoralation of GTP or the absence of a ligand
What is cyclic AMP?
a secondary messenger that is formed by cytosolic ATP by adenylyl cyclase (from the plasma membrae)
What happens to cAMP when the G protein becomes inactive?
adenylyl cyclase stops making new cAMP, the remains of cAMP is degraded to AMP by phosphodiesterase
What is the function of cAMP?
Its main target is protein kinase A (PKA) by regulating it by separating regulatory and catalytic subunits.
What is the function of PKA?
It phosphorylates a variety of proteins on serine or threonine residues, using ATP as a source of phosphate
What is IP3?
A second messenger generated by the activation of phospholipase C
How is IP3 formed?
PIP2 cleaved into IP3 and diacylgylcerol
Why is IP3 important?
it binds to the IP3 receptor that releases intracellular calcium
What do IP3 and diacylglycerol (DAG) activate?
Members of the protein kinase C family (PKC) which then phosphorylate ser and thr residues on a variety of proteins
Whats the function of calcium inside the cell?
It can cause ryanodine receptor channels to open allowing calcium to enter the cytoplasm from the ER and bind directly to calmodulin that binds to other proteins
What is the function of calmodulin?
When two Ca bind at each "hand" of calmodulin a comformation change occurs forming activated calcium calmodulin complex. In a presence of a protein the calmodulin wraps around its binding site.
What are protein kinase-associated receptors?
Receptors as well as act as kinases (when a ligand binds) they are either tyrosine kinases or serine/threonine kinases
What needs to happen for cell growth?
Growth factors have to bind sending a signal as well as enough nutrients
What do receptor tyrosine kinases often consist of?
a single polypeptide chain and a single transmembrane segment
What can happen upon binding of a ligand to tyrosine kinase receptors?
sometimes they can dimerize and phosphorylate each other
What is the dimerization and phosphorylation between two tyrosine kinase receptors called?
autophosphorylation
What can bond to phosphorylated tyrosine kinase?
SH2 domain
What is Ras?
molecule that is important in the regulation of cell growth, it is a small monomeric G Protein
What is the function of Ras?
can bind to GDP or GTP only active when bound to GTP. It require assistance from a guanine nucleotide exchange factor (GEF) called Sos
How does Sos become active?
It must bind the receptor through a protein called GRB2 which has an SH2 domain.
How can Ras release GDP and Bind to GTP, to activate it?
By Sos stimulating it after binding to GRB2
What happens after the activation of Ras?
A cascade of phophorylations
What is the first protein that is phosphorylated?
Raf, a protein kinase
What is the funciton of Raf?
to phosphorylate ser and thr residues in protein kinase called MEK
What is the function of MEK?
phosphorylates ser, tyr residues in a class of proteins called mitogen-activated protein kinases (MAP kinases) (activated called mitogen)
What is the function of MAPKs?
phosphorylate transcription factors that enter the nucleus to alter gene expression
What inactivates Ras?
The GTPase activating protein (GAP) facilitates GTP hydrolysis, allowing Ras to be bound to GDP and becomes inactive
What else can receptor tyrosine kinase activate and cause?
phospholipase C leading to the production of IP3 and DAG
What does phospholipase Cy contain?
SH2 domain
Serine-threonine kinases bind to what growth factor?
Transforming growth factor Beta (TGFbeta) and is good for apoptosis and embryonic cell development
What are the receptors TGFbeta can bind to?
Type I and Type II transmembrane receptors
What do some TGFbeta family members do?
they can dimerize before binding the receptors
Upon ligand binding what happens between the type I and type II receptors
the type II receptor phosphorylates the type I receptor causing a signal trandsudction cascade, phosphorylating a class of proteins call Smads
what are R-smads
smads that are phosphorylated by a complex of anchoring proteins and receptors
What is Smad 4
it forms a multiprotein complex with phosphorylated R-Smads; the whole complex enters the nucleus
What are hormones?
chemical signals secreted to coordinate the function of cells and tissues over long distances
where do endocrine hormones travel
circulatory system, long range
Where are endocrine hormones synthesized and then secreted
endocrine tissues and then secreted into the bloodstream
What are the functions of adrenergic hormones?
to put body functions on hold and redirect resources to the heart and skeletal muscles in dangerous or stressful situations
Where do adrenergic hormones bind?
G-protein linked receptors, adrenergic receptors calssified as a and b adrenergic receptors
What is the function of alpha-adrenergic receptors?
bind epinephrine and norepinephrine, located in smooth muscle regulating flow to visceral organs (contract)
What is the function of beta-adrenergic receptors?
bind epinephrine better than norephinephrine and are located on smooth muscles associated with arterioles feeding the heart, lungs, and skeletal muscles (dialate)
alpha-adrenergic are associated with what G protein
associated with Gq proteins, stimulate formation of IP3 and DAG
Beta adrenergic receptors are associated with what G protein?
activate Gs, which stimulates cAMP signal transduction
What happens with elevated calcium levels
Causes smooth muscle contraction, constricting blood vessels, and reducing blood flow
What cells in the pancreas secrete two peptide hormones to regulate normal glucose levels?
islets of Langerhans
What is the function of Glucagon
acts to increase blood glucose through glycogen breakdown
What is the function of insulin
reduces blood glucose levels by stimulation uptake into muscle and adipose cells stimulating glycogen synthesis
What does insulin bind to?
Tyrosine Kinases, which have two alpha and two Beta subunits
When insulin binds what happens?
The Beta subunits phosphorylate insulin receptor substrate I IRS-1
What are the two pathways IRS-1 stimulates?
recruit GRB2 activating Ras pathway and bind to phosphatidylinositol-3-kinase (PI-3 kinase) which converts PIP2 to PIP3 which then binds to a protein called Akt
What are the two consequences of Akt
leads to movement of a glucose transporter (GLUT4) to the plasma membrane allowing glucose uptake
Akt can phosphorylate glycogen synthase kinase 3 (GSK3) leading to an increase in the amount of active form of glycogen synthase, enhancing gycogen production