Nanomedicine, Volume I: Basic Capabilities
© 1999 Robert A. Freitas Jr. All Rights Reserved.
Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999
18.104.22.168 Natural Cellular Communications
Cells communicate chemically with each other in two ways -- contact signaling and secretory signaling. In the first category, chemical messages may be passed between cells in direct contact through gap junctions that directly join the cytoplasms of the interacting cells (Section 5.4.2). As in the case of foreign or self-antigen presentation (Sections 5.3.6 and 22.214.171.124), cells may also display plasma membrane bound molecules on their surfaces which may be "read" by other cells that come into physical contact with them. Signals may also be transduced into cells directly from the ECM.942,984-986
In the second category -- the principal focus of this Section -- there are four basic classes of secretory signaling molecules in the human body, as described briefly below and incompletely listed in Table 7.2. Normal human bloodstream concentrations of some of these molecules are given in Appendix B. At least several hundred different chemical messengers are known to be used in the human body, and many thousands may exist. Biologist Dennis Bray of Cambridge University believes that up to ~50% of the human genome may code for proteins involved in cell signaling,776 but 10%-20% for "classical" communication pathways is probably more reasonable. For example, the now-sequenced 97-megabase genome of the nematode Caenorhabditis elegans has ~19,099 protein-coding genes,3138 of which ~11% are involved in signal transduction and another ~11% in transport and secretion .3139
The first class of secretory signaling molecules is comprised of the endocrine hormones, which are usually secreted by exocytosis and travel through the bloodstream to distant target cells (e.g., "volume transmission") where they act as direct effectors on cell activity. For example, a steroid hormone, upon entering a target cell, binds to a complementary receptor protein. Binding induces conformational changes in the receptor and activates it, increasing the receptor's affinity for DNA and allowing it in turn to bind to specific genes in the nucleus, thus directly regulating their transcription.3140 This process is extremely wasteful because many activated receptors bind to DNA at sites where their presence has no effect;531 Lewin997 notes that activated receptors have a tenfold increased affinity for nonspecific DNA.
The second class consists of local chemical mediators or paracrines, which travel only a short distance (up to ~1 mm) to neighboring cellular targets. This group also includes the autocrines which act upon a cell's own receptors, such as the prostaglandins which are made by cells in all tissues. The single largest group in this class is the cytokines. Cytokines are soluble proteins or glycoproteins, produced by leukocytes and other cell types, which act as chemical communicators between cells but not as effector molecules in their own right.767 Cytokines include secretory peptides formerly classified as lymphokines, monokines, interferons, colony-stimulating factors, chemotactic factors and growth factors; over 150 different cytokines had been cloned by 1998.
The third class of chemical signaling molecules is the neurotransmitters, including the 60+ known neuropeptides (typically up to 30-40 residues long), which mediate communications between nerve cells and other cells. Interestingly, a single neurotransmitter signaling molecule may have different effects on different target cells. For instance, acetylcholine stimulates the contraction of skeletal muscle cells but decreases the contraction rate and force in heart muscle cells.531 The immune and neuroendocrine systems produce and respond to similar signal molecules (e.g., neuropeptides and cytokines). Neuropeptides have been shown to effect immune responses through their influence on cytokine production and action, and cytokines are known to induce or influence the production of peptidergic messenger substances.768
The fourth class is the intracellular messengers, also known as intracellular mediators or second messenger substances. While small hydrophobic signaling molecules like the steroids and thyroid hormones pass through the cell membrane and activate receptor proteins inside the cell, hydrophilic signaling molecules such as neurotransmitters, most hormones and local chemical mediators activate receptor proteins on the surface of the target cell. (Cell surface receptors for these signaling molecules may be either diffusely distributed or localized to specific regions of the membrane, and their number can vary from 500 to more than 100,000 per cell for a specific ligand.) Because cell surface receptors cannot regulate gene expression directly, they must emit a second messenger molecule into the cytosol which can then trigger the desired regulatory action. Cyclic AMP (cAMP), an intracellular messenger that tells certain types of cells to break down their glycogen stores in response to receipt of epinephrine at the cell surface, is perhaps the best-known example (Section 126.96.36.199). Another example is the voltage-gated Ca++ ion channel (Sections 3.3.3 and 188.8.131.52), which participates in nerve pulse events but also in signal transduction via the inositol-phospholipid pathway for more than 25 different types of cell surface receptors of hormonal signals.531 For instance, excitation-contraction coupling in skeletal muscle cells requires the release of Ca++ ions through ryanodine receptor channels in the SR (sarcoplasmic reticulum; Section 184.108.40.206), each of which opens to provide 48 picoamp Ca++ ion currents in 12 millisec bursts, through the SR membrane.1965
Last updated on 19 February 2003