Competitive - bind to the same spot as the agonist preventing binding of the agonist there by blocking the signal effected by agonist []

non-competitive - bind to a site different than the agonist and exert their negative effect from that site, not effected by agonist []

irreversible - bind covalently to a site on the receptor for ever, no effect from agonist []

Endocrine - long distances through the blood stream

Paracrine - cell releases message that is picked up by a neighboring cell

Autocrine- cell releases signal that is picked up by itself

Juxtacrine - cell signals by physical contact with an adjacent cell

type 1 - found in the cytoplasm binding of the hormone tells the receptor to travel into the nucleus

type 2 - found in the nucleus already

1. Receptor is activated by the hormone type 1 receptors are bound by heat shock proteins that are released upon hormone binding

2. Activated receptor binds to specific DNA sequences

3. Gene transcription is altered by the binding of the receptor

4 domains

6 transmembrane peices per domain s1-s6

s4 is positively charged and is a sensor that opens or closes a paddle on the channel to allow ions to pass

a loop between s5 and s6 is the selectivity filter that only allows specific ions to pass

some open or close based on appropriate charge being reached within the cell.

Ball and chain - As soon as s4 moves and opens the channel a ball and chain piece of the channel begins to move into place and arrives at its destination giving just enough time for some ions to pass through the channel as it is slower than the s4

4-5 subunits each with 4 domains.

M2 domains form pore

m1 domains bind to the ligand and undergoes a conformational change when the ligand binds spurring the channel to open

1.  Ligand dissasociates when the [] of ligand in the system drops

2.  Channel can be phosphorylated

7 membrane spanning domains

N terminus outside

C terminus inside

domains are all alpha helices

3 in 3 out loops

most ligands bind to the 3rd 4th or 5th domains

often exist as dimers hetero/homo constituitive or induced

1.  While bound to the ligand the GPCR becomes a target for G-Protein Receptor Kinase (GRK) which phosphorylates the portein making it a target for Arrestin, also stops interaction with g-protein.  It is then moved into a clatharin coated pit which becomes and endosome.  Low pH and phosphotases put the GPCR back in its original state. 

Occurs homologously - its own path starts this in motion

or

heterologously - another path starts this in motion

1.  Receptor phosphorylation leads to preferential degredation

2.  A decrease in translation/transcription

1.  Blocks receptor from binding g-protein

2.  Phosphorylate other proteins

3. Constituatively phosphorylate other receptors

4.  Constituatively phosphorylate other receptor interacting proteins

5.  decrease signaling by phosphorylating g-proteins

1.  GRK phosphorylate GPCR allowing arrestin to bind and direct them to clatharin pits to endosomes

2.  Arrestin bound to reseptors can also activate other signaling proteins independant of g-proteins

Heterotrimeric - three piece protein with an alpha subunit and a BY subunit

Monomeric - just one subunit which is similar to the alpha subunit of a heterotrimeric g-protein

1.  Ligand binds to GPCR and activates it causing a conformational change in it.

2.  The GPCR then acts as a GEF (guanine nucleotide exchange factor) on a g-protein.  This allows the alpha subunit of the g-protein to change conformation and dissasociate from a GDP and bind a GTP 

3.  Once bound to the GTP alpha disassociates from the BY subunits.

4.  Seperated from alpha BY are active as is the alone GTP bound alpha

1.  Reassociation of a GDP bound alpha with BY

2.  Phosphoducin can sequester independant BY

3.  Alpha can hydrolyze GTP to GDP eventually

4.  GAP can cause alpha to quickly hydrolyze GTP

Activate G-proteins independant of GPCR

Type1 - Act like a GEF much like a GPCR

Type II - Contain GPR (g-protein regulatory domains) bind to g-protein and remove alpha sequestering it and freeing up BY

Type III - sequesters BY not alpha

Sometimes called RAS genes involved mainly with cell growth and differentiation.  Fairly homogenious with three main parts:

Nucleotide binding

effector domain

GEF interacting domain

Turned on and off by many of the same type of stimuli as galpha subunits

Adenylate Cyclase

Phopholipase C (PLC)beta

Phosphodiesterases

Activation:

Forskolin

G-proteins

Protein Kinase C (PKC)

Ca2+

Calmodulin

Deactivation

G protein

PKA

Ca2+/Calmodulin

Ser/Thr kinase.  4 subunits 2 catalytic 2 regulatory.

2 cAMP bind each subunit and cause the catalytic subunits to disassociate and phosphorylate down stream targets.  Pseudo substrate sequence holds the regulatory domain close to the catalytic domain.  When cAMP binds to the protein, it autophospohorylates meaning very little cAMP is needed to cause the protein to activate.  Deactivates and binds back to regulatory subunit when the cAMP dissasociates.  Subunit targeted by PKA is very very specific. 

CREB

GPCR

Ion Channels

AC

activated by cGMP. 

Ser/Thr Kinase

2 homodomains each with 3 subunits.

Domain1 - suppresion of activity when no cGMP is around/mediate dimer binding and other protein interactions

Domain 2 - 2 non identical cGMP binding areas

Domain 3 - Catalytic domain

Hinged protein held together by a pseudo consensus sequence.

Important in muscle relaxing

Breaks down PIP2 a membrane bound phospholipid.  Splits PIP2 into DAG and IP3. 

EF - domain binds calcium

PH - binds the membrane often at a PIP3

X and Y - catalytic domains

Types of PLC

Beta - interacts with g-proteins alpha binds to C2 domain BY binds to the PH domain

Gamma - Can be activated by Receptor Tyrosine Kinases which phosphorylates it (RTK)

Phi? d` - ancestral form activated by calcium

Sigma - Ras activated "novel" as well as everything else

DAG lipase degrades it

DAG Kinase phosphorylates it and turns it into phosphotic acid which is a different messanger. 

Ser/Thr kinases

Consensus sequence is common so they are broad messangers

Conventional - activated by DAG Ca2+ PS(phosphotydalserine)

Novel - activated by DAG and PS no effected by Ca2+

Atypical - neither DAG PS or Ca2+ effect it, important in cell growth and apoptosis

1.  A hinged protein is closed

2.  PDK1 phosphorylates a domain near kinase domain

3.  2 autophosphorylation events occur

4.  Hinge is open

5.  Regulatory domains binds to a membrane via DAG or PS Ca2+ also involved

6.  Get some!

Protein interacting in C Kinase - Links PKC to PLC

InaD in a fruit fly rod connects all the proteins required for a signal cascade.  Allows for signal localization, without it the signal takes too long to occur. 

Golgi - processes proteins

Nucleus - cell proliferation anti apoptotic

Plasma Membrane - Growth and Immunity

DNA damage signal - caspases cleave off kinase domain and allow it to run wild

Cleaves IP2 into arachodonic acid which can be manipulated into highly important 2nd messangers.  

Activated by

GPCR bound to arrestin

RTK ->Ras Gef

Ion channel coupled receptor 

1.  Relaxin - increases cAMP levels.  PKC ^ = adenylate cyclase ^

2.  Contractile - increases Ca2+ Galphaq PLC IP3 ER Ca2+

3.  Ep3 - Increases Ca2+ decreases cAMP

FLAP shuttles AA to 5 LO which performs the first 2 steps of converting AA.  LTA4hydrolase finishes the job creating LTB4

Have a lot to do with inflammation

1.  Manipulation of [] by adding chemicals:

*ionophores bring Ca2+ accross the membrane allowing [] to increase according to the scientists wim

*Caelators act as Ca2+ sponges sucking up Ca2+

2.  Indicator dyes: Mostly change in flourescent spectrum when bound to Ca2+  Fura 2 is an example  

1.  Voltage Directed Calcium Channels allow calcium into the cell

2.  Calcium binds to the ryr channel along with cyclic adenosine diphosphate ribose (cADPR)  

also Ca2+ releases a hormone that then binds to a GPCR that activates AC that activates PKA that helps promote more VDCC

Binds to two Ca2+ and unfolds which allows an internal alpha helix to bind to other proteins.  

Binds to a ton of things:

AC

PDE

CAMKinase

1.  AP occurs and spreads down a T tubule

2.  Ca2+ is realeased from the Smooth Reticulum as a result

3.  Troponin is modified by Ca2+ and allows actin to be activated

4.  Hydrolosis of ATP allows actin myosin to do their thing

5.  Ca2+ put back into SR actin deactivated by troptonin