Biosignaling

SIGNALS

The ability of cells to receive and act on signals from beyond the plasma membrane is the fundamental to life.

The number of biological signals is multitude, as is the variety of biological responses to these signals, organisms use just a few evolutionary conserved mechanisms to detect extracellular signals and transduce them into intracellular changes.

The signals in animals may be:

A) Hormones produced in endocrine glands are secreted into the bloodstream and are often distributed widely throughout the body.

B) Paracrine signals are released by cells into the extracellular fluid in their neighborhood and act locally.

C) Neuronal signals are transmitted along axons to remote target cells.

D) Cells that maintain an intimate membrane-to-membrane interface can engage in contact-dependent signaling.

Many of the same types of signal molecules are used in endocrine, paracrine, and neuronal signaling. The crucial differences lie in the speed and selectivity with which the signals are delivered to their targets.

In all these cases, the signal is detected by a specific receptor and is converted to a cellular response.

Five Features of Signal -Transduction Systems

Cells receive external signals through sensing molecules — or receptors — (glycoproteins) embedded in the cell membrane. These, in turn, start a cascade of signaling molecules that carry the signals to the nucleus or other internal structures in the cell.

Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor

RECEPTORS - are proteins that occupy in the cell a strategic position

Amplification of external signal (through genome or second messengers) is the most important task of the reception

Properties of the receptors:

- the high-affinity hormone binding

- the high-affinity ligand binding

- limited coupling capasity

- specifisity of tissue localisation

- reversibility of the action

G protein-coupled receptor

Categories of cellular receptors

Channel-linked receptors

Channel-linked receptors have the receptor and transducing functions as part of the same protein molecule. Interaction of the chemical signal with the binding site of the receptor causes the opening or closing of an ion channel pore in another part of the same molecule. The resulting ion flux changes the membrane potential of the target cell and, in some cases, can also lead to entry of Ca2+ ions that serve as a second messenger signal within the cell.

Enzyme-linked receptors

Enzyme-linked receptors also have an extracellular binding site for chemical signals. The intracellular domain of such receptors is an enzyme whose catalytic activity is regulated by the binding of an extracellular signal. The great majority of these receptors are protein kinases, often tyrosine kinases, that phosphorylate intracellular target proteins, thereby changing the physiological function of the target cells.

G-protein-coupled receptors

G-protein-coupled receptors regulate intracellular reactions by an indirect mechanism involving an intermediate transducing molecule, called the GTP-binding proteins (or G-proteins). Hundreds of different G-protein-linked receptors have been identified. Well-known examples include the β-adrenergic receptor, the muscarininc type of acetylcholine receptor, metabotropic glutamate receptors, receptors for odorants in the olfactory system, and many types of receptors for peptide hormones.

Intracellular receptors

Intracellular receptors are activated by cell-permeant or lipophilic signaling molecules. Many of these receptors lead to the activation of signaling cascades that produce new mRNA and protein within the target cell. Often such receptors comprise a receptor protein bound to an inhibitory protein complex. When the signaling molecule binds to the receptor, the inhibitory complex dissociates to expose a DNA-binding domain on the receptor. This activated form of the receptor can then move into the nucleus and directly interact with nuclear DNA, resulting in altered transcription. Some intracellular receptors are located primarily in the cytoplasm, while others are in the nucleus. In either case, once these receptors are activated they can affect gene expression by altering DNA transcription.

Signaling Through the Membrane

Signal amplification results in a tremendous increase in the potency of the initial signal permits precise control of cell behavior.

Some biologically active compounds can penetrate into the cell and interact with intra-nucleolus receptors affecting the RNA synthesis.

Steroid Hormones Bind Receptors in Nucleus

G Protein-Coupled Receptors

These receptors associate with trimeric G proteins bound to the inside of the cell membrane. The G proteins consist of three subunits. The  subunit binds GDP or GTP. Receptor binding triggers  conformational change which causes the a subunit to separate from the  subunits and to exchange its GDP for GTP. Both the G -GTP and free G  complexes can diffuse along the membrane and either stimulate or inhibit their targets. The targets may either be enzymes such as adenylyl cyclase which generates the second messenger cAMP or channels which induce membrane depolarization. When GTP on G  is hydrolyzed to GDP and Pi, it reassociates with G  and the "switch" is turned off.

How G Proteins Work

The first step in this complex signalling system involves the binding of specific ligands (hormones, neurotransmitters, growth factors, glycoproteins, cytokines, odorants and photons) at the cell surface to a GPCR, thereby activating the receptor.

The signal is transmitted into the cell via a conformational change in the receptor, which results in the activation of the bound G protein. GPCRs act as guanine nucleotide exchange factors for the a subunit of the G protein, whereby activated receptor promotes the exchange of bound GDP (guanine diphosphate) for GTP on the a subunit, which is the rate-limiting step in G protein activation. The binding of GTP changes the conformation of ‘switch’ regions within the a subunit, which allows the bound trimeric G protein (inactive) to be released from the receptor, and to dissociate into active a subunit (GTP-bound) and bg dimer. The a subunit and the bg dimer go on to activate distinct downstream effectors, such as adenylyl cyclase, phosphodiesterases, phospholipase C, Src, and ion channels.

These effectors in turn regulate the intracellular concentrations of secondary messengers, such as cAMP, cGMP, diacylglycerol, IP3, DAG, arachidonic acid, sodium, potassium or calcium cations, which ultimately lead to a physiological response, usually via the downstream regulation of gene transcription.

The cycle is completed by the hydrolysis of a subunit-bound GTP to GDP, resulting in the re-association of the  and  subunits and their binding to the receptor, which terminates the signal.

Second Messengers

Second messengers that mediate activation of adrenergic and cholinergic receptors binding the visceral organs effector cells :

1. cyclic adenosine monophosphate (cAMP)

2. cyclic guanosine monophosphate (cGMP)

3. inositoltriphosphate (IP3)

4. diacylglycerol (DAG).

5. Ca2+ ions

6. nitric oxide (NO)

7. hydrogen sulfide (H2S)

, etc.

Adenylyl Cyclase Mechanism

The adenylyl cyclase system works in the following steps:

- a hormone or neurotransmitter binds to a surface receptor which creates a conformational (shape) change with the receptor itself

- the conformational changes causes the α subunit of the G protein to detach (disassociate)

- the α subunit interacts with another membrane protein/enzyme called adenylyl cyclase; this activates the adenylyl cyclase enzyme

adenylyl cyclase converts adenosine triphosphate (ATP) into cAMP

- cAMP binds with a specific protein that is called a kinase (cAMP dependent kinase)

- This activates a cascade of enzymatic pathways leading to the cellular response to the hormone

ATP will continue to be converted into cAMP as long as the hormone and recepter remain bound. When the hormone is detached from its receptor this system goes in reverse and shuts down

Since cAMP is directly activating the cellular responses it is considered the secondary messenger.

cAMP Formation and Inactivation

Chemical messages that utilize this system are: adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid stimulating hormone (TSH), antidiuretic hormone (ADH), human chorionic gonadotropin (HCG), melanocyte-stimulating hormone (MSH), corticotropin-releasing hormone (CRH), beta 1 and beta 2 receptors, calictonin, parathyroid hormone (PTH), glucagon.

Adenyl Cyclase and Phosphodiesterase Reactions

Protein kinase A regulate activity of a variety of proteins

Signal Transduction Cascade Involving Cyclic AMP

alpha1-adrenoceptors are found on the cell membranes of smooth muscle, liver, salivary glands, and sweat glands, and on nerve cells in the central nervous system. When activated, they stimulate a sequence of chemical events of which the end result is mainly the release of calcium ions inside the cell, and this in turn mediates the final action.

αalpha2-adrenoceptors are sited on nerve endings, both in those neurons that use noradrenaline as their neurotransmitter and other neurons that do not. They can also be found on smooth muscle where they mediate contraction. In the CNS, stimulation of α2-adrenoceptors lowers blood pressure and causes sedation and even unconsciousness. The sequence of events that follows activation of α2-adrenoceptors results in a reduction in the formation of cyclic adenosine monophosphate (cAMP) and this in turn mediates the ultimate effect.

βbeta1-adrenoceptors are the most important adrenoceptors in the heart, where they mediate increase in heart rate and force. They relax gut smooth muscle, cause breakdown of fat, and cause amylase secretion from salivary glands. On nerve endings, they increase transmitter release. β

beta2-adrenoceptors are on smooth muscle, including blood vessels, bronchioles, uterus, bladder, and the iris, where they mediate relaxation. They cause tremor in skeletal muscle (shivering) and the breakdown of glycogen in the liver to release glucose into the blood, and decrease histamine release from mast cells.

An example of a signal transduction cascade involving cyclic AMP

The binding of adrenaline to an adrenergic receptor initiates a cascade of reactions inside the cell. The signal transduction cascade begins when adenylyl cyclase, a membrane-bound enzyme, is activated by G-protein molecules associated with the adrenergic receptor. Adenylyl cyclase creates multiple cyclic AMP molecules, which fan out and activate protein kinases (PKA).

Protein kinases can enter the nucleus and affect transcription

AKAPs target PKA and other molecules to a wide range of subcellular structures

A-kinase anchoring proteins (AKAPs) target protein kinase A (PKA) to specific compartments, including the plasma membrane, mitochondria, cytoskeleton and centrosome19. Within a compartment, the same AKAP can associate with different substrates. Alternatively, different AKAPs within the same compartment can assemble distinct signalling complexes. In addition to binding to PKA, AKAPs can interact with other signalling molecules. One category includes signal-termination enzymes such as phosphatases that counterbalance kinase activity, or phosphodiesterases (PDEs) that degrade cyclic AMP and limit PKA activation.

Adenosine receptor family in CNS is an example of cooperative action on adenylate cyclase activity

There are three types of guanylate cyclases th...

Phospholipases and Phospholipids in Sign...

Phosphoinositide Cascade

Receptor Tyrosine Kinase Pathway

The receptors for many polypeptide growth factors and hormones are proteins with a single transmembrane domain and an intrinsic tyrosine kinase activity.

Those receptors include epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Insulin-like growth factor receptor (IGFR), a dimeric receptor, is also another tyrosine kinase receptor.

Several Members of the Receptor Tyrosine Kinase (RTK) Family

Tyrosine kinase inhibitors – are anticancer drugs