Paracrine & endocrine communications

The neuronal synapse and the gap junction are one extreme in a signaling spectrum. At the other end are the endocrine or systemic signaling systems.

Between these two extremes are juxtacrine or neighboring and paracrine or local signaling systems

Typically, endocrine signals are secreted by cells directly into the blood stream, travel throughout the body and effect many different cell types.

These signaling molecules fall into two generic types, hydrophilic and hydrophobic molecules.

Hydrophilic signaling molecules, or ligands, act by binding to receptor proteins on the surface of target cells. Hydrophobic ligands are transported through the blood stream attached to a hydrophilic carrier. When released, they can pass through the membrane and bind to intracellular receptors.

Adrenaline, for example, is a hydrophilic molecule that is secreted into the blood stream in response to stress, while testosterone is a hydrophobic signaling molecule involved in the development of male sexual characteristics.

Adrenaline activates G-protein coupled receptors in many different tissues. It mediates the 'fight or flight" response.

Secreted by the adrenal glands in response to stress, it

• increases heart rate
• decreases blood flow to certain tissues
• increases blood flow to other tissues, such as skeletal muscles
• increases blood glucose and
• alters mental functioning

G-protein signaling

This is an indirect adapter system by which the binding of ligand to a receptor is coupled to the regulation of various downstream enzymes.

The system is centered around a ligand-binding receptor and a G-protein.

G-proteins are trimers composed of and regulatory subunits and a -catalytic subunit.

All three are anchored to the cytoplasmic face of the plasma membrane by helical tails.

The subunit is a GTP binding/GTPase.

In response to the binding of ligand to receptor, the G-protein complex binds to the receptor. The GDP bound to is replaced by a GTP.

This leads to the disassembly of the G-protein complex.

The -GTP polypeptide moves along the plasma membrane and interacting with various membrane proteins.

As long as the ligand is bound to the receptor, more and more G-proteins are activated.

When the -GTP polypeptide binds to target enzymes it acts as an allosteric effector.

In the case of adenylate cyclase, -GTP binding activates the enzyme and leads to the production of cyclic AMP from ATP.

cAMP acts as a second messenger - the first messenger is the ligand that bound to the surface receptor.

cAMP acts as an allosteric effector. For example, it binds to protein kinase A (PKA) and activates it.

PKA in turn can phosphorylate and regulate the activities of various other proteins.

This creates a protein kinase cascade.

G-protein signaling effects end when

• the ligand dissociates from the receptor
• the GTP-bound to the subunit is hydrolyzed to GDP
• the levels of second messengers decrease.
• the effects of these second messengers are reversed.

Where phosphorylation is involved, the phosphates are removed by specific phosphotases.

Hydrophobic signaling molecules

Whereas hydrophilic signaling molecules travel freely through the bloodstream, but require membrane proteins to influence their target cells.

Hydrophobic signaling molecules can pass through membrane, but require water soluble carrier proteins to travel through the blood stream.

There are a number of different hydrophobic signaling molecules: the include the steroid hormones and the retinoids.

Steroids are derived form cholesterol, while retinoids are derived from vitamin A.

Both steroids and retinoids regulate gene expression in a similar manner.

The pass through the plasma membrane, and interact with intracellular receptor proteins.

They are allosteric effectors of these receptors.

The activated receptor complex binds to specific DNA sequences and acts to regulate the transcription of specific genes.

NO signaling

Another type of hydrophobic signaling pathway is that characterized by the nitrogen oxide or NO pathway.

NO is a gas and can diffuse through the plasma membrane. NO is generated from arginine.

The best understood site of NO signaling is in blood vessels.

NO is generated by endothelial cells and diffuses into the surrounding muscle tissue.

This enzyme generates cyclic GMP from GTP.

cGMP acts on the muscle's contractile system, leading to relaxation.

The diameter of blood vessels is regulated by smooth muscle cells that are wrapped around the vessel's endothelium or inner cell lining.

If the muscle constracts, the vessel is constricted and less blood can flow through it. As the muscle relaxes the vessel opens and more blood flows.

Viagra (sildenafil) works by inhibiting the enzyme phosphodiesterase, that breaks down cGMP.

It keeps the muscles relaxed.

Nitroglycerin, which is used to treat circulatory problems, breaksdown into NO and glycerin. It supplies NO which leads to the relaxation of vascular muscles and the opening of blood vessels.

Signaling networks

In the case of signaling systems that alters gene expression, there are two levels of response.

There are those genes whose expression is directly regulated. These are the primary response genes.

There are also genes whose expression is regulated by the primary response gene products.

Signaling systems are interconnected networks that share common targets and in some cases common components.

This results in non-linear feedback and feedforward loops, and complex cellular and organismic behaviors.