Second messenger system

Submitted by: Ankumoni DuttaM.Sc 3rd sem.Roll no-7

Introduction Second messengers are molecules that relay signals

received at receptors on the cell surface — such as the arrival of protein hormones, growth factors, etc. — to target molecules in the cytosol and/or nucleus. Second messengers serve to greatly amplify the strength of the signal.

History• Earl Wilbur Sutherland, Jr., discovered second messengers, for

which he won the 1971 Nobel Prize in Physiology or Medicine.• Sutherland saw that epinephrine would stimulate the liver to

convert glycogen to glucose (sugar) in liver cells, but epinephrine alone would not convert glycogen to glucose.

• He found that epinephrine had to trigger a second messenger, cyclic AMP, for the liver to convert glycogen to glucose.

• The mechanisms were worked out in detail by Martin Rodbell and Alfred G. Gilman, who won the 1994 Nobel prize.

Second messenger systems There are three major class of second messenger

systems:

• Adenylyl Cyclase–cAMP Second Messenger System.• The Cell Membrane Phospholipid Second Messenger

System.• Calcium-Calmodulin Second Messenger System

Adenylyl Cyclase–cAMP Second Messenger System

• Some of the hormones that achieve their effects through cAMP as a second messenger: adrenaline, glucagon , luteinizing hormone (LH).

• Binding of the hormone to its receptor activates • a G protein which, in turn, activates adenylyl cyclase. • The resulting rise in cAMP turns on the appropriate response in the cell

by either (or both): – changing the molecular activities in the cytosol, often using Protein

Kinase A (PKA) — a cAMP-dependent protein kinase that phosphorylates target proteins;

– turning on a new pattern of gene transcription.

Cyclic GMP (cGMP)

• Cyclic GMP is synthesized from the nucleotide GTP using the enzyme guanylyl cyclase. Cyclic GMP serves as the second messenger for :

• atrial natriuretic peptide (ANP) • nitric oxide (NO) • the response of the rods of the retina to

light.• Some of the effects of cGMP are mediated

through Protein Kinase G (PKG) — a cGMP-dependent protein kinase that phosphorylates target proteins in the cell

The Cell Membrane Phospholipid Second Messenger System.

• Peptide and protein hormones like vasopressin, thyroid-stimulating hormone (TSH), and angiotensin and neurotransmitters like GABA bind to G protein-coupled receptors (GPCRs) that activate the intracellular enzyme phospholipase C (PLC).

• it hydrolyzes phospholipids — specifically phosphatidylinositol-4,5-bisphosphate (PIP2) which is found in the inner layer of the plasma membrane.

• Hydrolysis of PIP2 yields two products: Inositol trisphosphate (IP3) and diacylglycerol (DAG)

….contd• DAG remains in the inner layer of the plasma membrane. It recruits Protein

Kinase C (PKC) — a calcium-dependent kinase that phosphorylates many other proteins that bring about the changes in the cell. The lipid portion of DAG is arachidonic acid, which is the precursor for the prostaglandins and other local hormones that cause multiple effects in tissues throughout the body.

• Inositol-1,4,5-trisphosphate (IP3) This soluble molecule diffuses through the cytosol and binds to receptors on the endoplasmic reticulum causing the release of calcium ions (Ca2+) into the cytosol. calcium ions then have their own second messenger effects, such as smooth muscle contraction and changes in cell secretion.

Calcium-Calmodulin Second Messenger System

This second messenger system operates in response to the entry of calcium into the cells.

Normally, the level of calcium in the cell is very low (~100 nM). There are two main depots of Ca2+ for the cell:

• The extracellular fluid (ECF — made from blood), where the concentration is ~ 2 mM or 20,000 times higher than in the cytosol;

• the endoplasmic reticulum ("sarcoplasmic" reticulum in skeletal muscle).

….contdIn response to many different signals, a rise in the concentration of Ca2+ in the

cytosol triggers many types of events such as• muscle contraction; • exocytosis, e.g.,

– release of neurotransmitters at synapses.– secretion of hormones like insulin

• activation of T cells and B cells when they bind antigen with their antigen receptors (TCRs and BCRs respectively)

• adhesion of cells to the extracellular matrix (ECM) • apoptosis • a variety of biochemical changes mediated by Protein Kinase C (PKC).

…contd

However, its level in the cell can rise dramatically when:

• channels in the plasma membrane open to allow it in from the extracellular fluid or

• from depots within the cell such as the endoplasmic reticulum and mitochondria.

…..contd

Getting Ca2+ into (and out of) the cytosol:• Voltage-gated channels open in response to a change in membrane

potential, e.g. the depolarization of an action potential; are found in excitable cells:

– skeletal muscle – smooth muscle (These are the channels blocked by drugs, such as felodipine

[Plendil®], used to treat high blood pressure. The influx of Ca2+ contracts the smooth muscle walls of the arterioles, raising blood pressure. The drugs block this.)

– neurons. When the action potential reaches the presynaptic terminal, the influx of Ca2+ triggers the release of the neurotransmitter.

– the taste cells that respond to salt.

….contd

• Receptor-operated channels These are found in the post-synaptic membrane and open when they bind the neurotransmitter. Example: NMDA receptors.

• G-protein-coupled receptors (GPCRs). These are not channels but they trigger a release of Ca2+ from the endoplasmic reticulum. They are activated by various hormones and neurotransmitters (as well as bitter substances on taste cells in the tongue

…..contd

• On entering a cell, calcium ions bind with the protein calmodulin.

• The calmodulin changes its shape and initiates multiple effects inside the cell, including activation or inhibition of protein kinases.

• Activation of calmodulin-dependent protein kinases causes, via phosphorylation, activation or inhibition of proteins involved in the cell’s response to the hormone.

….contd

• The normal calcium ion concentration in most cells of the body is 10-8 to 10-7mol/L, which is not enough to activate the calmodulin system. But when the calcium ion concentration rises to 10-6 to 10-5 mol/L, enough binding occurs to cause all the intracellular actions of calmodulin.

• This is almost exactly the same amount of calcium ion change that is required in skeletal muscle to activate troponin C, which causes skeletal muscle contraction.

Reference

Guyton and Hall, text book of medical physiology, eleventh edition; Pg: 912- 915

Second messenger system - Wikipedia, the free encyclopedia.html

Second Messenger Systems at the US National Library of Medicine Medical Subject Headings (MeSH)

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