Cyclic AMP PathwaySecond Messenger

Continuation of Cell Communication

ARIANE RUBY B. SOGO-AN

Objectives :

• Explain the role of the Primary and SecondaryMessengers in the cAMP Pathway

• Determine the steps during the cAMPpathway.

Communication

• How important is communication in our everyday life?

– Achieving productivity

– Maintaining strong relationships

– Understand each other

– Make the proper response

Cell Communication/Signalling

• Critical for the function and survival of cells that compose a multicellular animal.

– Ways/modes:

• Adjacent Cells – Gap junctions

• Specific contact between cells – Specific molecules on cell surface

• Through intercellular chemical messengers

Second Messengers

• Second messengers are intracellular signallingmolecules released by the cell to triggerphysiological changes suchas proliferation, differentiation, migration,survival, and apoptosis.

• Secondary messengers are therefore one ofthe initiating components ofintracellular signal transduction cascades.

INTRODUCTION

• Second messengers are molecules that relay signals from receptors on the cell surface in accordance to the type of first messenger to produce biochemical signal to target molecules inside the cell.

• They greatly amplify the strength of the signal, cause some kind of change in the activity of the cell.

• They are a component of cell signaling pathways.

Second messengers

• Short lived intracellular signaling molecules

• Elevated concentration of second messenger leads to rapid alteration in the activity of one or more cellular enzymes

• Removal or degradation of second messenger terminate the cellular response

• The cell releases second messenger molecules in response to exposure to extracellular signals - the First messengers.

• Because hormones and neurotransmitters typically comprise biochemically hydrophilic molecules, first messengers may not physically cross the phospholipid bilayer cell membrane to initiate changes within the cell directly.

• This functional limitation necessitates the cellto devise signal transduction mechanisms totransduce first into second messengers, sothat the extracellular signal may bepropagated intracellularly.

• An important feature of the secondmessenger signaling system is that secondmessengers may be coupled downstream tomulti-cyclic kinase cascades to greatly amplifythe strength of the original first messengersignal.

Signalling sequence in the Target Cell

• Reception

– Binding of a signal molecule with a specific receptor of the target cells.

• Transduction

– Process of changing the signal into the form necessary to cause the cellular response. May or may not include cascade of reaction that includes several different molecules.

Signalling sequence in the Target Cell

• Response

– Transduced signal causes a specific cellular response.

Steps in Communication Via Extracellular signals

1. Synthesis

2. Release of the signalling molecule by the signalling cell

3. Transport of the signal to the target cell

4. Binding of the signal by a specific receptor protein leading to its activation

5. Initiation of one or more intracellular signal transduction pathways by the acticvatedreceptor

6. Specific changes in the cellular function, metabolism and development

7. Removal of the signal

Cell Communication/Signalling

• Cell communication systems based on surface receptors have three (3) components:

– The extracellular signal molecules released by controlling cells

– The surface receptors on target cells that recieves the signals

– The internal response pathways triggered when the receptors binds a signal.

Intercellular chemical messengers

• One cell “Controlling Cell” synthesizes specific molecule that acts a signaling molecule to affect the activity of another cell called the target cell.

• Example:

– In response to stress, cells of mammal’s adrenal gland secrets hormones ephinephrine into the bloodstream. Epinephrine acts on target cells to increase the amount of glucose in the blood.

Ligand Binding to it complementary cell Receptor

The signaling molecule acts as a ligand, which binds to a structurally

complementary site on the extracellular or membrane-spanning

domains of the receptor.

Overview of seven major classes of cellsurface receptors

GASES

NO

H2S

CO

HYDROPHOBIC

Diacylglycerol

Phosphatidylinositols

HYDROPHILIC

cAMP

cGMP

IP3

Ca2+.

TYPES OF SECOND MESSENGERS

• The binding of ligands (“first messengers”) tomany cellsurface receptors leads to a short-lived increase (or decrease) in theconcentration of certain low-molecular-weightintracellular signaling molecules termedsecond messengers.

• Other important second messengers are Ca2 and various inositol phospholipids, also called phosphoinositides, which are embedded in cellular membranes.

Four common intracellular second messengers.

More receptors using the same second messenger system

Reception

The G Protein Coupled Receptor

ALL (GPCRs) contain seven membrane-spanning regions with their N-terminal segment on the exoplasmic face and their C-terminal segment on the cytosolic face of the plasma membrane

Schematic diagram of the general structure of G protein–coupled receptors.

• The signal-transducing Gproteins contain threesubunits designated , , and .During intracellular signalingthe and subunits remainbound together and areusually referred to as the Gsubunit.

• The G subunit is a GTPaseswitch protein thatalternates between an active(on) state with bound GTPand an inactive (off) statewith bound GDP

The ability of a G protein to interact with other proteins and thus transduce a signal differs in the GTP-bound “on” state and GDP-bound “off” state.

• These guanine nucleotide–binding proteins are turned “on” when bound to GTP and turned “off” when bound to GDP. Signal-induced conversion of the inactive to active state is mediated by a guanine nucleotide–exchange factor (GEF), which causes release of GDP from the switch protein.

• Subsequent binding of GTP, favored by its highintracellular concentration, induces aconformational change in two segments of theprotein, termed switch I and switch II, allowingthe protein to bind to and activate otherdownstream signaling proteins.

• The intrinsic GTPase activity of the switchproteins then hydrolyzes the bound GTP to GDPand Pi, thus changing the conformation of switchI and switch II from the active form back to theinactive form. The rate of GTP hydrolysisfrequently is enhanced by a GTPase-acceleratingprotein (GAP)

Hormone-induced activation and inhibition of adenylyl cyclase in adipose cells.

Conversion of ATP to cAMP

Protein Kinase A

Synthesis and degradation of glycogen.

Regulation of glycogen metabolism by cAMP in liver and muscle cells.

Mechanisms Regulate Signalingfrom G Protein–Coupled Receptors

• 1. The affinity of the receptor for hormone decreases when the GDP bound to Gs is replaced with a GTP following hormone binding.

• 2. The GTP bound to Gs is quickly hydrolyzed, reversing the activation of adenylyl cyclase and production of cAMP.

• 3. cAMP phosphodiesterase acts to hydrolyzecAMP to 5-AMP, terminating the cellular response.

• The intracellular levels of cAMP are regulated by the balance between the activities of two enzymes: adenylyl cyclase (AC) and cyclic nucleotide phosphodiesterase (PDE).

• When a Gs protein–coupled receptor is exposed to hormonal stimulation for several hours, several serine and threonine residues in the cytosolic domain of the receptor become phosphorylated by protein kinase A (PKA).

• The phosphorylated receptor can bind its ligand, but ligand binding leads to reduced activation of adenylyl cyclase; thus the receptor is desensitized.

• This is an example of feedback suppression, in which the end product of a pathway (here activated PKA) blocks an early step in the pathway (here, receptor activation).

Role of -arrestin in GPCR desensitization and signal transduction.

END OF REPORT