Water soluble messenger/receptor pathways

camp inhibition

- some do get inhibited by the first activation this occurs because there are different g proteins that stimulate or inhibit which regulat intracellular camp

Signaling by G-protein Coupled Receptors

-bound to the inactive receptor is a protein complex located on the cytosolic surface of the plasma membrane and belonging to the family of heterotrimeric (containing three different subunits) proteins known as G‐proteins. •-All intact G‐protein complexes contain three subunits, called the alpha, beta and gamma subunits. The alpha subunit can bind GDP and GTP. The beta and gamma subunits help anchor the alpha subunit in the membrane. - The binding of a ligand to the receptor changes the conformation of the receptor. • This activated receptor increases the affinity of the alpha subunit of the G protein for GTP. -When bound to GTP, the alpha subunit dissociates from the beta and gamma subunits. -This dissociation allows the activated alpha subunit to link up with another plasma membrane protein, which may be either an ion channel or an enzyme. -These ion channels and enzymes are called plasma membrane effector proteins because they mediate the next steps in the sequence of events leading to the cell's ultimate response.

How does the increased CA++ concentration elicit the cells responses?

-common point of ca++ is its ability ot bind to various vytosolic proteins altering their conformation thereby activating their function - one of the most important protein found in all cells is calmodulin -when ca binds to calmodulin it changes shape causing ca++ to activate or inhibit a large variety of enzymes and other proteins , many of them being kinases

Signaling by receptors that function as enzymes

-these receptors are known as receptor tyrosine kinases 1.binding of the ligand to the receptor alters the receptors shape which activates its enzyme function, phosphorylation an intracellular protein -2.binding of receptors causes autophosphorylation of the recepetor, receptor phosphorylates some of its own tyrosine residues 3. the new phosph. tyrosines serve as docking sites for cytoplasmic proteins 4. these cytoplasmic proteins activate one or more singaling pathways in the cells - ALL pathways involve activation of cytoplasmic proteins by phosphorylation EXCEPTION: the plasma membrane protein in this instance doesn't serve its kinase function no phosphorlytation receptor functions and receptor and gunnel cyclase to catalyze the formation of cGMP cGMP acts as second messenger then goes on to active cGMP protein Kinase this phosphorylates some other cells then leads to cells response NO common first messenger

example

1. Binding of a first messenger to the receptor changes the conformation of receptor 2. active receptor increases affinity for alpha subunit of the g protein for gap 3. when bound to gtp the alpha subunit dissociates from the better and gimme subunits 4.dissoc makes alpha link with another plasma protein, channel or enzyme (effector proteins) effect what happens next (GTP to GDP) causing alpha sub unit to come off nd recombine with better and gemme ion channel: ca++ in enzyme: activate or inactivate the membrane enzyme it interacts with

CAMP pathway

1. activation of receptors by binding the first messenger ( ex epinephrine) allows the receptor to activate its assoc. g protein. 2. this causes g protein to activate its effector enzyme which is adenyl cyclase 3. adenyl cyclase with catalyitic site in cytosol catalyzes the conversion of cyto. ATP to camp 4. camp acts as a second messenger 5. diffuses throughout the cell to trigger the sequence the cells ultimate response to the first messenger

Camp inactivation

1terminates when broken down to AMP catalyzed via CAMP phosphodiesterase - this enzyme subject to control cellular concentration of cAMp can be changed either by altering the rate of its messenger mediated synthesis or the rate of its phosphodiesterase mediated break down.

How do stimuli cause the cytosolic concentration of ca++ to increase?

Active transport system in the plasma membrane of certain causes ca++ to maintained at an extremely low concentration in the cytosol causing a large gradient favoring diffusion into the cytosol via ca++ channels found in PM and ER stimulus to the cell can alter this steady state by influencing the active transport system and or ion channels resulting ina change in cytosolic ca++ concentration

what happens to CA++ when IP3 binds?

Because concentration of CA++ its higher in the ER than in the cytosol it diffuses out to cytosol -increasing CA++ concentration - the increase of CA++ concentrations leads to cells response of first messenger -ca++ helps activate some forms of protein kinase C

Opening of voltage gated calcium channels

Calcium binds to calmodulin. On binding calcium, the calmodulin changes shape, which allows it to activate or inhibit a large variety of enzymes and other proteins. Many of these enzymes are protein kinases. II. Calcium combines with calcium-binding intermediary proteins other than calmodulin. These proteins then act in a manner analogous to calmodulin III. Calcium combines with and alters response proteins directly, without the intermediation of any specific calcium-binding protein.

Major second messengers

Camp Phospholipase Ca++

Camp and cellular response

Cells can respond via the cAMP pathways using a diversity of cAMP‐dependent enzymes, channels, organelles, contractile filaments, ion pumps, and changes in gene expression. -A G protein activates plasma membrane adenyl cyclase which catalyzes the formation of CAMp from ATP effect: Activates kamp-dependent protein kinase

CA++ Signaling 1. Receptor Activation

Receptor activation A. Plasma-membrane calcium channels open in response to a first messenger; the receptor itself may contain the channel, or the receptor may activate a G protein that opens the channel via a second messenger. B. Calcium is released from the endoplasmic reticulum; this is mediated by second messengers, particularly IP3 and calcium entering from the extracellular fluid. C. Active calcium transport out of the cell is inhibited by a second messenger.

Receptors that are bound to and activate cytoplasmic JAK kinases: Kinase Coupled Receptors plays a role in

The Janus kinases (JAK) are a family of 4 tyrosine kinases. • A variety of receptors proteins associate with various members of the JAK kinase family. • The result of the JAK activated pathways is the synthesis of new proteins, which mediate the cell's response to the first messenger. • example: Signaling by cytokines—proteins secreted by cells of the immune system that play a critical role in immune defenses—occurs primarily via receptors linked to JAK kinases

ca++ Caldumulin

The calcium-calmodulin system is similar to some of the cAMP pathways, because it results in the activation via phsphorlyation of protein kinases that can phosphorylate key proteins required for cellular response Example: Activates the contraction of smooth muscle

Phospholipase C

This receptor-G-protein complex is linked to and activates phospholipase C, leading to an increase in IP3 and DAG, which work together to activate enzymes and to increase intracellular calcium levels.

DAG

activates members of a family of related protein kinases called protein kinase c then phosphorylates a large number of other proteins leading to the cells response

Effect if CA++

activates protein kinase c, calmodulin, and other CA++ binding proteins CAlmodulin activates calmodulin dependant protein kinases

Signaling by receptors that are ligand gated ion channels where is it prevalent

binding of the ligand to the receptor alters the receptors shapre which then opens or closes an ion channel the protein that acts as a receptors is also an ion channel -prevelant in neurons and skeletal muscle -results in an increase in the net diffusion of ions across the membrane EXAMPLE: change in ion diffusion results in change in membrane potential causing ca to diffusion into cytosol increasing cystolic ca ca++

IP3

doesn't exert its second messenger function by directly activating a protein kinase cystolic IP3 binds to receptors located on ER these receptors are ligand boiund CA ++ channels that open when bound to IP3 releases CA++ from ER into the cytosol

source of CA++

enters cell through plasma membrane ion channels or is released into the cytosol from ER

Function of Calcium ion

functions as a second messenger ina great variety of cellular responses to stimuli both chemical and electrical

Process of Phospholipase C

g protein activated via first messenger then g activates a plasma membrane effector called phospholipase c this catalyzes the break down of plasma membrane phospholipid known as PIP2 to DAG and IP3 both DAG and IP3 function as second messengers

cGMP

genereated from GTP in a reaction catalyzed by a plasma membrane reveptor with guanlyl cyclase activity effects: activates cgMP dpendent protein kinase g

Soo really what does the activation of adenyl cyclase do

initiates amplification cascade of events that converst proteins in sequence from inactive to active forms - while its active a single enzyme molecule is capable of transforming into product not but many substrate molecules -end results is that a single molecule of the first messenger could generate of 1 million product molecules

cell surface receptors act as:

ion channels enzymes receptors coupled to kinases receptors that are coupled to g protein: activate g protein then in turn act upon effect proteins (either ion channels or enzymes) in plasma membrane -camp -phospholipase C -Arachnodonic Acid

What does cAMP do inside the cell?

it binds to and acticates an ensymes known as camp dependant protein kinase/protein kinase a the changes in activity of proteins phosphorylated by camp dependent protein bring about a cells response, secretion contration e.g

camp dependant protein kinase can p

phosphorylate certain plasma membrane ion channels therefore cacusiong them to open or clause OR again act as enzyme and going with phosphorylation

summary of mechanisms by which receptor activation influences ion channels

the ion channel is part of the receptor a g protein directly gates the ion channel a g protein gates the ion channel indirectly via production of a secon messenger such as camp