Signaling via Hydrophobic Molecules

Hydrophobic molecules can move in and out of cells by passing through lipid bilayers.  Nitric oxide, arachidonic acid and steroids have been shown to play important roles in cell signaling.

Figure 6-B-1.  Signaling with NO or arachidonic acid.  Unlike most signaling cascades which occur within the same cell, newly generated NO or arachidonic acid diffuses to act on target molecules in neighboring cells. 

Nitric oxide

Nitric oxide (NO) is produced from the following reaction:

where NOS represents NO synthase.  After NO is generated in a cell, it diffuses to act on target molecules in neighboring cells.  NO may stimulate soluble guanylyl cyclase to produce cGMP which regulates several enzymes and ion channels.  In smooth muscle, an important action of cGMP is to induce muscle relaxation.  Normally, cGMP will soon be converted into GMP by phosphodiesterase.  The well known drug for impotence, Viagra (sildenafil citrate), inhibits phosphodiesterase.

Figure 6-B-2.  Structures of cAMP and cGMP.

Review Articles:

The Biology of Cyclic GMP-dependent Protein Kinases -  J. Biol. Chem., 2005.

Cyclic GMP-Dependent Protein Kinases and the Cardiovascular System - Circulation Research, 2003.

Regulation of Gene Expression by Cyclic GMP - Circulation Research, 2003.

Nitric Oxide and Cardiac Function - Circulation Research, 2003.

Regulation of Nitric Oxide-Sensitive Guanylyl Cyclase - Circulation Research, 2003.

Physiology of Nitric Oxide in Skeletal Muscle - Physiological Review, 2001.

Pharmacology of Penile Erection - Physiological Review, 2001.

Oxygen Reduction by Nitric-oxide Synthases - J. Biol. Chem., 2001.

Cyclic GMP Phosphodiesterase-5: Target of Sildenafil - J. Biol. Chem., 1999.

Arachidonic acid

Arachidonic acid is generated from phospholipid hydrolysis catalyzed by phospholipase.  Like NO, its target is usually not located in the cell where it was first generated.  After diffusing to target cells, arachidonic acid may activate protein kinase, resulting in phosphorylation of target molecules.  Many of its target molecules are involved in learning and other neuronal activities. 

Figure 6-B-3.  Generation of arachidonic acid from phospholipid by phospholipase A₂ (PLA₂).

Review Article:

Arachidonic acid as a bioactive molecule - J. Clinical Investigation, 2001.

Epoxygenase Pathways of Arachidonic Acid Metabolism - J. Biol. Chem., 2001.

Steroids

The major role of steroids is to regulate transcription, since many steroid receptors are transcription factors.  

Figure 6-B-4.  A transcriptional activation mechanism by steroid receptor (SR).  Steroid-bound SR may recruit SRC (steroid receptor coactivator) and histone acetyltransferases to stimulate transcription of the target gene (see also Figure 4-G-3).  In the absence of the steroid, several steroid receptors may recruit corepressors (e.g., SMRT and NCoR) and histone deacetylases to repress transcription.