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Signal Transduction at Cell Membranes: Protein Kinases and Phosphotases

Lastly, we will consider general mechanisms for signal transduction across membranes of any cell that must respond to its environment. Typically the agent that signals a cell to respond is a molecule (or in the case of light sensation a photon) which binds either to a cell surface receptor or to a cytoplasmic receptor if the signaling agent is hydrophobic. In almost all cases, such signaling activates protein kinases in the cell.

Kinases are a class of enzymes which use ATP to phosphorylate molecules within the cell.

The names given to kinases shows the substrate which is phosphorylated by the enzyme. For example:

  • Hexokinase - an enzyme that uses ATP to phosphorylate hexoses.  
  • Protein kinase - enzymes that use ATP to phosphorylate proteins within the cell. (Note: Hexokinase is a protein, but is not a protein kinase).
  • Phosphorylase kinase: an enzyme that uses ATP to phosphorylate the protein phosphorylase within the cell.

In this chapter we will review the activation by extracellular signals of 5 different protein kinases within the cell. These kinases phosphorylate other proteins within the cell and through associated conformational and charge changes, the phosphorylated proteins are either activated or inhibited in the expression of biological activity.

If a protein is phosphorylated by a kinase, the phosphate group must eventually be removed by a phosphatase through hydrolysis. If it wasn't, the phosphorylated protein would be in a constant state of either being activated or inhibited. Kinases and phosphatases regulate all aspects of cellular function. Some people estimate that 1-2% of the entire genome may encode kinases and phosphatases. We will review only the properties of five major protein kinases which are activated through interactions with different ligands. The mechanisms of activation of the different types of kinases will be described below. Keep in mind that there appears to be about 518 different protein kinases in humans.

Figure:five major protein kinases


Kinases and Their Activation

1. Protein Kinase A (PKA):

Cascade of events: A transmembrane receptor WITHOUT ENZYMATIC ACTIVITY binds an extracellular chemical signal, causing a conformational change in the receptor which propagates through the membrane. The intracellular domain of the receptor is bound to an intracellular heterotrimeric G protein (since it binds GDP/GTP) in the cell. The G protein dissociates and one subunit interacts with and activates an enzyme - adenylate cyclase - which converts ATP into a second messenger - cyclic AMP (cAMP) - in the cell. cAMP activates protein kinase A (PKA) which phosphorylates proteins at specific Ser or Thr side chains. 

Figure: cyclic AMP


Receptors which work through an intermediary G protein usually are single polypeptide chains that span the membrane seven times in a serpentine fashion.



Some signals that activate adenylate cyclase and use cAMP as a second messenger include: corticotrophn, dopamine, epinephrine (b-adrenergic), follicle-stimulating hormone, glucagon, many odorants, prostaglandins E1and E2, and many tastants.


Some enzymes regulated by cAMP-dependent phosphorylation by PKA

Enzyme Pathway
Glycogen Synthase glycogen synthesis
Phosphorylase Kinase glycogen breakdown
Pyruvate Kinase Glycolysis
Pyruvate Dehydrogensae Pyruvate to acetyl-CoA
Hormone-sensitive Lipase Triacylglyeride breakdown
Tyrosine Hydroxylase Synthesis of DOPA, dopamine, norepinephrine
Histone H1 Nucleosome formation with DNA
Histone H2B Nucleosome formation with DNA
Protein phosphatase 1 Inhibitor 1 Regulation of protein dephosphorylation
CREB cAMP regulation of gene expression
PKA cosensus sequence XR(R/K)X(S/T)B(B = hydrophobic amino acid)

An example of how epinephrine (a flight/fight hormone) can lead to breakdown of glycogen (your main carbohydrate reserves in muscle and liver) is shown below. A cascade of events, starting with the binding of the hormone to its receptor, followed by activation of adenylate cyclase, which forms cAMP, which activates PKA, which leads to the activation of the enzyme that breaks down glycogen (glycogen phosphorylase) is shown. (For simplicity, G protein involvement is not shown.)

Figure:Activation of glycogen phosphorylase through activation of PKA.


2,3. Protein Kinase C (PKC) and Calmodulin-Dependent Kinase (CAM-PK)

Cascade of Events: A transmembrane receptor WITHOUT ENZYME ACTIVITY binds an extracellular chemical signal, causing a conformational change in the receptor which propagates through the membrane. The intracellular domain of the receptor then binds to an intracellular heterotrimer G protein (since it binds GDP/GTP) in the cell. The G protein dissociates and one subunit interacts with and activates an enzyme - phospholipase C - which cleaves the phospho-head group from a membrane phospholipid - phosphatidyl inositol - 4,5-bisphosphate (PIP2) into two second messengers - diacylglyerol and inositol trisphosphate (IP3). Diacylglycerol binds to and activates protein kinase C (PKC). The IP3 binds to ligand-gated receptor/Ca++ channels on internal membranes, leading to an influx of calcium ions into the cytoplasm. Calcium ions bind to a calcium modulatory protein, calmodulin, which binds to and activates the calmodulin-dependent kinase (CAM-PK). The released calcium ions also activate PKC. As in the previous example, these receptors which interact with G proteins are single polypeptide chains which contain 7 membrane spanning alpha helices. The cycle of degradation and resynthesis of PIP2 is called the PI cycle.

Figure:PI cycle


Some signals that activate phospholipase C and make IP3 and diacylglycerol include: acetylcholine (a different class than the type located at the neuromuscular junction that we discussed in the last chapter section), angiotensin II, glutamate, histamine, oxytocin, platelet-derived growth factor, vasopressin, gonadotropin-releasing hormone, and thyrotropin-releasing hormone. Some proteins phosphorylated by PKC include:

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Some kinases regulated by calcium and calmodulin include: myosin light chain kinase, PI-3 kinase, and CAM-dependent kinases. Ca/CAM also regulates other proteins which include: adenylate cyclase (brain), Ca-dependent Na channel, cAMP phosphodiesterase, calcineurin (phosphoprotein phosphatase 2B), cAMP gated olfactory channels, NO synthase, and plasma membrane Ca/ATPase.

4. Receptor Tyrosine Kinases: Cascade of Events

A transmembrane receptor WITH HORMONE-DEPENDENT ENZYMATIC ACTIVITY (tyrosine kinase) binds an extracellular chemical signal, causing a conformational change in the receptor which propagates through the membrane. The intracellular domain of the receptor becomes an active tyrosine kinase which can phosphorylate itself (autophosphorylation) or other proteins.  Such kinases are usually active in a multimeric state. Typically, binding of two molecules of a ligand or a ligand dimer to individual subunits of the receptor causes the monomers of the receptor to dimerize. In this form the kinase activity of the receptor is activated. The individual subunits of the multimer are proteins with a single transmembrane helix. Examples are the insulin receptor and epidermal growth factor receptor.

Receptor Tyr kinases autophosphorylate themselves, in a process required for their activity. When the receptor is autophosphorylated, other proteins can bind to the cytoplasmic domain of the receptor Tyr kinase where they are phosphorylated. The target substrates phosphorylated by the receptor Tyr kinase are proteins with a common 100 amino acid domain called SH for src homolgy, based on structural homology to another cytoplasmic protein, Src. Src is an intracellular Tyr kinase activated when it binds through 2 SH domains to the autophosphorylated receptor Tyr kinase. Specifically, the SH2 domain has been shown to bind phosphorylated peptides. These domains target proteins to the autophosphorylated receptor Tyr kinase. 

Figure:Receptor/Ligand-Dependent Protein Kinases


Many proteins involved in signal transduction have SH2 domains. Some of these proteins also have catalytic domains with kinase activity. Others have phosphatase, transcription factor. or scaffolding domains.

5. Protein Kinase G (PKG): Cascade of Events:

A transmembrane receptor OR a cytoplasmic protein WITH LIGAND-DEPENDENT ENZYMATIC ACTIVITY (guanylate cyclase) binds an extracellular chemical signal (for the transmembrane receptor) or an intracellular ligand (for the cytoplasmic protein receptor), causing a conformational change in the receptor. The bound receptor is now a guanylate cyclase which converts GTP into cyclic GMP. This second messenger, like cAMP which binds to and activates PKA, binds to and activates the cGMP-dependent protein kinase (PKG). An example of a hormone which works through a transmembrane receptor is atrial naturetic factor, which binds to a cell-surface receptor whose shape change is communicated to the intracellular receptor domain through the single transmembrane helix, leading to the activation of the intracelluar guanylate cyclase domain of the protein. Likewise, nitric oxide, NO, a gaseous ligand formed from Arg, can diffuse through the cell membrane, where it binds to the heme of a cytoplasmic receptor/guanylate cyclase which form cGMP, leading to activation of PKG. (Steroid hormones also enter the cell where they interact with a cytoplasmic receptor which often acts as steroid hormone-dependent transcription factor. )

Kinases can be classified in many other ways. One is substrate specificity: Eukaryotes have different kinases that phosphorylate Ser/Thr or Tyr. Prokaryotes also have His and Asp kinases but these are unrelated structurally to the eukaryotic kinases. There are 11 structurally different families of eukaryotic kinases, which all fold to a similar active site with an activation loop and catalytic loop between which substrates bind. Simple, single cell eukaryotic cells (like yeast) have predominantly cytoplasmic Ser/Thr kinases, while more complex eukaryotic cells (like human) have many Tyr kinases. These include the membrane-receptor Tyr kinases and the cytoplasmic Src kinases.

Recently, Manning et al. have analyzed the entire human genome (DNA and transcripts) and have identified 518 different protein kinases, which cluster into 7 main families as shown in the chart below. Family membership was determined by sequence comparisons of catalytic domains. They have named the entire repertoire of kinases in the genome the kinome. Alterations in 218 of these appear to be associated with human diseases.

The Kinome



AGC Contain PKA, PKG, and PKC families
CAMK Ca2+/CAM-dependent PK
CKI Casein kinase 1
CMGC Contain CDK, MAPK,GSK3, CLK famiies
STE homologs of yeast sterile 7, 11,20 kinases; MAP Kinase
PTK Protein tyrosine kinase
PTKL Protein tyrosine kinase-like
RGC Receptor guanylate kinase


There are three main families of phosphatases: the phospho-Tyr phosphatases (PTP), the phospho-Ser/Thr phosphatases, and those that cleave both. They can also be categorized by the molecular sizes, inhibitors, divalent cation requirements, etc. In contrast to kinases which differ in the structure of their catalytic domains, many phosphatases gain specificity by binding protein cofactors which facilitate translocation and binding to specific phosphoproteins. The active phosphatase hence often consists of a complex of the phosphatase catalytic subunit and a regulatory subunit. Regulatory subunits for Tyr phosphatases may contain a SH2 domain allowing binding of the binary complex to autophosphorylated membrane receptor Tyr kinases.

Important Ser/Thr phosphatases include:

  • Protein phosphatase 1 (PP-1) - different regulatory subunits target this to the liver glycogen particles or muscle sarcoplasmic reticulum

  • Protein phosphatase 2A (PP-2A) - is a trimer with catalytic, regulatory, and a scaffolding structural subunits. 

  • Protein phosphatase 2B (PP-2B) - also called calcineurin or Ca2+/Calmodulin dependent protein phosphatase. It consists of a catalytic subunit (calcineurin A) and a regulatory, calcium-binding subunit (calcinerin B). It is inhibited by the complex of the immunosuppressant cyclosporin and FK506 with immunophilins. PP2B regulates PKA and PKC

  • Protein phosphatase 2C (PP-2C) -

PP1, 2A and 2B share a great deal of amino acid homology, and based on this homology, belong to one family. PP2C belongs to another. 

Protein Tyr phosphatases (PTPs) consist of receptor-like (transmembrane) and intracellular Tyr phosphatases. They more resemble tyrosine kinases in their complexity than the Ser/Thr phosphatases. There are about 100 PTPs that have an active site Cys in aCX5R-(S/T) motif. Important examples include:

  • PTP1B - dephosphorylates many cell surface receptors (insulin, EGF, PDGF) that have been phosphorylated on Tyr residues. Its main activity seems to dephosphorylate nascent receptors in the endoplasmic reticulum before they get to the final cell membrane destination. 

  • Low molecular weight PTPase - These have roles in metabolism and differentiation of cells. They have a molecular weight of 18,000 and have an active site CX5R-(S/T) motif, where the C (Cys) is an active site nucleophile. Human adipocyte acid phosphatase is an example.

Receptors and G Proteins

Receptors that interact with G proteins often have common characteristics. Consider the b-adrenergic receptor, a prototype for such receptors. These bind epinephrine and adrenaline, are found in muscle, liver, and fat cells, and are activated when energy reserves in these tissues are mobilized. The receptors are single polypeptides which have 7 membrane-spanning a- helices. Over 1000 similar serpentine receptor genes are found in humans, each encoding a protein of similar topology but which bind different ligands. Many of the receptors bind to unknown ligands, and hence are called orphan receptors. 

The unoccupied adrenergic receptor is associated with a heterotrimeric G protein, which contains an a, b, and g subunits. GDP is usually bound to the a subunit. When the hormone is bound to the receptor, interactions of the receptor with the G protein (probably through the b andg subunits) leads to conformational changes in the G protein leading to replacement of GDP with GTP. This promotes dissociation of the a subunit (with bound GTP), which is then free to bind to and activate adenylate cyclase, an adjacent membrane protein. The a subunit is held to the membrane through a lipid anchor attached through a post-translational modification. As long as GTP remains bound to the Gasubunit, it will continually activate adenylate cyclase. There needs to be a method to reverse this process, otherwise no regulation of the process could occur. A built in regulatory mechanism does exist, since the Gasubunit has GTPase activity. The GTP will eventually hydrolyze, the GDP-Gasubunit will lose affinity for adenylate cyclase, and return to for the heterotrimeric G protein associated with the unbound receptor. 

Some bacterial toxins work by inactivating the GTPase activity of the Gasubunit, keeping it in the "stuck" position. For example, cholera toxin, an enzyme released by Vibrio cholerae, catalyzes the ADP ribosylation of an Arg in the Gasubunit by transferring everything but the nicotinamide from NAD+ to the Arg residue.

In contrast to the beta-adrenergic receptor, some Gasubunits actually inhibit adenylate cyclase when bound. These Gasubunits are called Gi in contrast to the stimulatory subunits, Gs. Some Gasubunits interact with proteins other than adenylate cyclase. We have already seen an example with the PKC activation of phospholipase C. There are many different Ga-like subunits expressed in different tissues. 

Examples of different signals, receptors, Galike-subunits, second messenger changes, and affected intracellular enzymes

signal vasopressin epinephrine light odorant odorant sweet tastant
receptor VR b-adrenergic rhodopsin odorant recep. 1 odorant recept. 2 sweet receptor
Galike- subunit Gi Gs transducin Golfactory Golfactory Ggustatory
coupled enzyme adenylate cyclase adenylate cyclase phosphodiesterase phopholipase C adenylate cyclase adenylate cyclase
2nd messenger decrease cAMP increase cAMP decrease cGMP increase IP3 increase cAMP increase cAMP
protein affected decrease PrK-A increase PrK-A dec. Ca, Na perm. inc. Ca perm inc.Ca, Na perm dec. K perm

Another variant of a G protein is the protein ras. Mammalian cells contain 3 variants of ras: H, K, and N. They all bind GDP/GTP and have GTPase activity, and are members of a large familty of small GTPase proteins. This protein is targeted to the cell membrane through the post-translational addition of a hydrophobic farnesyl group. When activated by binding to GTP, it can bind a GAP protein (GTPase activating protein) called Raf-1, which has tyrosine kinase activity. 

It is often the case that occupied receptors activate protein kinases, which activate other protein kinases, which activate yet other protein kinases to produce phospho-proteins which may act as transcription factors. An example is the mitogen activated protein kinase (MAPK system). A mitogen is an external chemical signal that causes mitosis or cell division. Activation of transcription factors by their phosphorylation through a mitogen activated kinase is required. The sequence of events is:

  • binding of external signal to membrane receptor and activation of receptor kinase
  • phosphorylation of receptor kinase and interaction with an activator G-protein like ras
  • binding of activated G-protein to and activation of a mitogen activated protein kinase kinase kinase (MKKK)
  • MKKK phosphorylates and activates another kinase, MKK
  • MKK phosphorylates and activates mitogen activated protein kinase, MAPK
  • MAPK phosphorylates inactive transcription factors and activates them

Two specific example of such a cascade of activations are illustrated below.

External Signal/Receptor
Generic Names
Growth Factor/Growth Factor Receptor Integrin/Integrin Receptor
Activator G protein Ras:GTP Rac1:GTP
Protein Target c-Jun c-Jun

The Receptome

There are an enormous variety of membrane receptor proteins in human cells. In analogy to the genome, glycome, proteome, lipome, interactome and kinome, the human receptome has been shown to contain 20 different families containing over 1000 different receptors. 

  • 7 TM (transmembrane) receptors and GPCR
  • Toll
  • NPR
  • Integrins
  • LDL receptors
  • Notch
  • Patched
  • Plexins
  • Roundabout
  • RPTPs
  • RTKs
  • Ser/Thr Kinase receptors
  • TNF receptors
  • Cytokine 1 receptors
  • T-cell receptors
  • Cytokine 2 receptors
  • Netrin receptors

Information about these receptors can be found at theStanford Human Plasma Membrane Receptor web site. 

Regulation by Phosphorylation

The activity of many different proteins (receptors, enzymes, channels) are regulated by phosphorylation by kinases, and dephosphorylation by phosphatases. The most critical role for phosphorylation is probably in the regulation of cell growth, division, and death. The cell cycle describes the various stages in the life of a cell.

The cell cycle is divided into time intervals as shown in the diagram below. S stands for DNA synthesis, M for mitosis (cell division), and G1 and G2 for gaps in between DNA synthesis which occurs in S and mitosis which occurs in M. The diagram shows the cycle for a typical eukaryotic cell that is actively dividing. Some cells enter a quiescent phase (Go) which represent a terminally differentiated cell, which may require months to divide.

Figure:Cell Cycle


Passage through the cell cycle depends on the presence in the cell of two kinds of proteins:

  • cyclins: which accumulate in the cell at various stage of the cell cycle and hence rise and fall in cyclic fashion
  • cyclin-dependent protein kinases which form complexes with the cyclins to control their activity

For example, in frogs, cyclin dependent protein kinase 2 (CDK2) binds to cyclin B to form an active kinase which phosphorylates a prereplication complex initiating S phase and mitosis. Cyclin B, a 45Kd protein, accumulates to high levels just before S phase. Its concentration drops sharply at the end of mitosis. The kinase, a 34 Kd protein, is encoded by the CDC2 gene (for cell division cycle gene). A homologous gene exists in humans - the CDK2 gene (cyclin dependent kinase 2) - and controls entry in S phase. These kinases can be considered heterodimers with a kinase catalytic subunit and a cyclin regulatory subunit. In animal cells, there are at least ten different cyclins (A, B, .....) and at least eight different cyclin-dependent kinases (CDK1-8).

Signal Transduction and Reactive Oxygen Species

We have previously shown that the redox state of a cells affects protein folding and disulfide bond formation as well as the health of a cell. It should not be surprising then that the redox state of a cell is regulated and also that the redox state of a cell regulates cell activity. Consider a reactive ROS and potent oxidizing agent, hydrogen peroxide. We have described the potential deleterious effects of this molecules on lipids, nucleic acids, and proteins. At the same time, it can act to protect a cell. This is clearly seen in the case of immune cells like neutrophils, which can engulf microorganisms, and kill them, in part through generation of ROS like hydrogen peroxide formed after an oxidative burst of activity. Hydrogen peroxide is generated in neutrophils through the action of NADPH oxidase (Nox), which catalyzes the production of NADP and H2O2 from NADPH + O2. The neutrophil must be protected from the effects of the H2O2 which rises to mM concentrations, but destruction of H2O2 must be minimized while it acts to kill the microorganism. Nox, a membrane protein found on the cell membrane, produces H2O2. It's also found in phagosomes, which contain Nox from the cell membrane. For H2O2 to regulate cell activity, it must translocate into the cytoplasm. Cytoplasmic H2O2 has been shown to regulate signal transduction pathways by chemically modifying Cys residues in key signal transduction proteins. Phosphatases, which contain an active site Cys in a Cys-XXXX-R catalytical loop, can be reversibly oxidized by H2O2. The Arg side chain decreases the pKa of the active site Cys, making it a better nucleophile toward phospho-tyrosine substrates and more susceptible to H2O2 oxidation. This inhibition, which can be reversed on addition of thiols, is also observed on stimulation of cells with various external signaling ligands and leads to anincrease in the phosphorylation state of proteins, altering signal transduction pathways. These changes correlate with increased cytoplasmic H2O2. In addition, it has been shown the oxidation of two Cys side chains in Src, a protein kinase, activated the enzyme in a process that correlates with the appearance of H2O2. 

For these H2O2-dependent events to occur, the H2O2 must be protected from enzymes like catalase, but more importantly peroxiredoxin, which is found in the cytoplasm. These enzymes have been shown to react with two H2O2 molecules, which inactivate them as one of the two Cys is coverted from RSH to RSO2-. (Rhee, 2006) Another eukaryotic protein, sulfiredoxin, can reverse this inhibition.

Nox is assembled in highly specific subcellular regions of the membrane such as lipid rafts and focal complexes (between the cell and the extracellular matrix). H2O2 is imported into the cell. For some membranes H2O2 is easily diffused across the membrane, but recent studies have shown other membranes lack this permeability. In this case aquaporin may regulate the transfer. Furthermore, Nox protein assembly has been discovered in organelle membranes such as the endoplasmic reticulum and nucleus. H2O2 produced in these regions is held within the lumen of the organelle.

Another Look at Neurotransmission and Ion Channels

You may have noticed above that some signaling molecules, whose effects are regulated by kinases (b-adrenergic and some olfactory signals by PKA and acetylcholine by PKC for example), are neurotransmitters. In the previous chapter section, we discussed how neurotransmitters can act as signals to open ion-specific, ligand-gated membrane channels, which change the transmembrane potential. In other words, the neurotransmitters gate the channels directly. Typical examples of channels directly gated by neurotransmitters are the acetylcholine receptor in neuromuscular junctions and the Glu, Gly, and GABA receptors in the central nervous system. These receptors are multimeric proteins. Receptors with direct gating of ion flow are fast, with activities that last milliseconds, and are used in eliciting behavioral responses.

However, ion channels can also be gated indirectly when the neurotransmitter binds to its receptor and leads to events which open an ion channel that is distinct from the receptor. In this case, the occupied receptor communicates to an ion channel indirectly through a G protein. Example of this indirect gating of ion channels include the serotonin, adrenergic, and dopamine receptors in the brain. These receptors are classic single protein serpentine receptors with 7 transmembrane helices, and intracellular domains that can interact with G proteins as described above to increase second messenger levels (cAMP, DAG) in the neuron. These can either activate kinases in the cell, which phosphorylate ion channels to either open or close them, or can bind directly to the channel and modulate its activity through an allosteric conformational change. In some cases the G protein directly acts on the ion channel. These different ways are described below. In contrast to direct gating, receptors that indirectly gate ion channels have activities that are slow and last seconds to minutes. These receptors are usually involved in modulating behavior by changing the excitability of neurons and the strength of neural connections, hence modulating learning and memory. These changes can occur in many ways, summarized below and in the following link:

Figure:Neurotransmission:Gating through G Linked Receptors


Phosphorylating ion channels: Receptors that act through a second messenger system can change ion channel activity by activating kinases which phosphorylate the channels. This may:

  • open the channel normally closed at the resting potential and produce an effect like gating.

  • close a channel usually open at the resting potential (such as nongated K channels which when closed would depolarize the cell and make it more excitable).

Gainteraction with ion channels: 

Second messenger interaction with ion channels:  

  • cGMP opens cation channels in retinal cells after activation of the photoreceptor by photons

  • cAMP opens cation channels in olfactory cells after activation of the olfactory receptor by odorants.

Second messenger effects on proteins other than ion channels (usually different receptors): 

  • the b-adrenergic receptors are phosphorylated by PKA and PKC (activated by stimulation of a different neurotransmitter receptor linked through a G protein to produce increased levels of second messengers cAMP and diacylglycerol). When phosphorylated, the b-adrenergic receptor (itself activated through G protein) can't bind Gs. This in effect attenuates the response of the b-adrenergic receptor to its own neurotransmitter which leads to desensitization to that signal. 

Second messenger regulates gene expression:

  • cAMP activated PKA can phosphorylate an inactive transcription factor in the cell, which then can bind to a section of DNA called the cAMP Response Element (CRE), which is upstream of certain genes, leading to the transcription of the genes. The transcription factor is called CREB forcAMP Response Element Binding protein. Example: tyrosine hydroxylase (a monooxygenase) is involved in the synthesis of epinephrine and norepinephrine. The activity of this protein is increased when it is phosphorylated by PKA. Hence its activity can be increased quickly by this modification of the already present protein. If an animal is subjected to severe or long term stress (cold or immobilization), presynaptic cells with norepinephrine will be stimlulated to release the neurotransmitter. This requires continual synthesis of the neurotransmitter by the presynaptic cell. The increase in synthesis of this neurotransmitter is caused by the presynaptic cell being stimulated by another neuron, whch leads to increased levels of cAMP, and ultimately activation of CREB which increases transcription of the hydroxylase gene. 


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