Signaling by increasing cytosolic calcium is an important and ubiquitous intracellular coordination mechanism. We already saw that release of Ca2+ in muscle cells is required to allow contraction of each sarcomere, and the positioning of the sarcoplasmic reticulum makes possible rapid changes in concentration nearly simultaneous across the entire cell. Another extremely important physiological mechanism that relies on calcium is fertilization. Immediately upon penetration of the egg by the sperm, a wave of intracellular Ca2+ increase spreads across the egg starting from the point of fertilization. This activates CaMKII (a kinase) and calcineurin (a phosphatase). Both are needed to overcome meiotic arrest and may also be necessary in initial embryonic development by control of chromatin decondensation, nuclear-envelope formation, and the movement and fusion of the two nuclei.
The aforementioned CaMKII is Ca2+/calmodulin-dependent kinase II, and illustrates a fairly common theme, which is the use of Ca2+-binding proteins as intermediate Ca2+ sensing activators. Calmodulin is a ubiquitous calcium-binding protein in eukaryotes and its importance is highlighted by the extraordinarily high homology across species. In normal cytosolic Ca2+ levels, the relatively low affinity of the 4 Ca2+ binding sites on calmodulin are unfilled. But when Ca2+ concentrations rise, they occupy the sites, causing a conformational change in calmodulin and allowing it to interact with other proteins. In addition to calmodulin, troponin-C, and PKC, a few other important calcium-sensitive proteins are calsequestrin, a Ca2+ buffer protein, gelsolin, the f-actin severing enzyme, the protease calpain, and calretinin, an activator of guanylyl cyclase (which makes the second messenger cGMP).
Guanylate (guanylyl) cyclase is also an important player in signal transduction by nitric oxide (NO). Nitric oxide is a gas produced by the action of nitric oxide synthase (NOS) on the substrate amino acid arginine. It is used as a super-soluble signal that passes through cells easily. However, it requires relatively high concentrations for physiological effect, so it is strictly a paracrine factor working on near neighbors. Perhaps the best studied example of NO signaling is vasodilation, in which the NOS-expressing endothelial cells of a blood vessel release NO to the smooth muscle cells surrounding them. The NO binds to and stimulates guanylate cyclase. The resulting increase in cGMP concentration leads to relaxation through multiple targets of protein kinase G.
Sildena l (Viagra) and its chemical siblings take advantage of this pathway by inhibiting cGMP-specific phosphodiesterases (PDE5) which normally break down cGMP to limit the response to NO. However, it should be noted that though PDE5 expression is limited, it is expressed not only in the genitalia but in the retina as well.
Finally, no discussion of signal transduction would be complete without at least a fleeting mention of the extraordinary crosstalk (fig. 12) that can occur between the different pathways mentioned.
Figure 12. Signal transduction in actin dynamics. This figure comes from Cell Signaling Technology, Inc.
The figure represents only one small part of the signaling that happens inside a moving cell. Not only are some parts of the cell forming filopodia to help determine where to go, other parts or ruffling up the lamellipodia, and still others inducing motor proteins to rearrange the cytoskeleton in the proper way to facilitate bulk transport internally even as the leading edge of the cell is thrusting forward to make contacts externally. All of this must be coordinated by crosstalk between signaling systems as depicted, not to mention signaling related to metabolism, or gene expression, or even cell cycle, all of which are happening simultaneously inside the cell.