Biochemistry: Chemical Reactions in Living Cells, Volume 1 - D. Metzler 1980

Membranes and Cell Walls
Antigens and Receptors on the Cell Surface

Many biochemists are currently focusing on how Cell surfaces interact with other biological entities. For instance, membrane surfaces carry specific groupings that act as Antigens. Antigens are distinct chemical structures that trigger The production of Antibodies capable of binding to them specifically. Approximately 250 different antigenic groupings (determinants) have already been identified On the surface of an erythrocyte. These determinants define Blood type, while similar determinants found on the surfaces of other Cells dictate whether transplanted tissue will be rejected. Various Proteins from plants and other sources act as agglutinins, binding to surface groupings in a manner similar to antibodies. Viruses that attack cells adsorb to specific surface receptors, which may be identical to certain antigenic determinants. It is of particular interest to understand how certain cells "decide" that other cells are "foreign." Heightened interest in this issue stems from the fact that solving it could pave the way for preventing tissue rejection reactions and treating severe autoimmune diseases (Ch. 16, Sec. B.7).

Appendix 5-D

Calcium

The essential role of Calcium Ions in living organisms was first discovered in the last century by Ringer, who established that maintaining contractions in a perfused Heart

requires $\text{Ca}^{2+}$ ions at a concentration of ~ 1 $\mu$M. Later, the crucial role of calcium was demonstrated in repairing cellular damage in the protozoan Stentor and in amoeboid movement. In the absence of calcium, these organisms quickly perish. Studies on the frog heart revealed that $\text{Ca}^{2+}$ ions are involved in transmitting nerve impulses from nerves to The cardiac Muscle.

Like $\text{Na}^+$ ions, $\text{Ca}^{2+}$ ions are actively extruded from cells^a,b. The bulk of calcium in The Human Body is located in the bones^c-e. In human blood serum, the concentration of $\text{Ca}^{2+}$ ions is 2.5 $\mu$M, of which approximately 1.5 $\mu$M is in the free form, while the remainder is bound to proteins, CARBOHYDRATES, and Other Compounds. Inside cells, the concentration of free calcium is even lower. For example, the total concentration of $\text{Ca}^{2+}$ ions in erythrocyte Cytoplasm is about 3 $\mu$M, yet free ions account for less than 1 $\mu$M. The concentration gradient of $\text{Ca}^{2+}$ ions across the membrane (ranging from $10^2$ to $10^5$) is maintained by the calcium pump. The pump's action is counteracted by a very slow passive back-diffusion of ions into The Cell.

A characteristic function of $\text{Ca}^{2+}$ ions in living organisms is their ability to activate various metabolic processes. This occurs during sharp Changes in the permeability of Plasma Membranes or Endoplasmic reticulum membranes, which allow $\text{Ca}^{2+}$ ions to diffuse into the cytoplasm. For instance, During Muscle contraction, the release of $\text{Ca}^{2+}$ ions from The endoplasmic reticulum raises its concentration from roughly 0.1 to 10 $\mu$M^e. The binding of $\text{Ca}^{2+}$ ions to troponin C initiates contraction (Ch. 4, Sec. E.1)^f. The membranes of muscle fiber endoplasmic reticulum contain an Abundance of calcium pump protein as well as several calcium-binding proteins (Ch. 4, Sec. B.8.c)^g. One such $\text{Ca}^{2+}$-binding protein from rabbit muscle, calsequestrin (mol. wt. 46,500), can bind up to 43 moles of $\text{Ca}^{2+}$ per mole of protein^h,i.

Another trigger function of calcium is the release of Neurotransmitters from nerve terminals (at synapses). In most cases, the initiation of an impulse in the postsynaptic neuron is preceded by an increase in $\text{Ca}^{2+}$ ion concentration within the synapse (Ch. 16, Sec. B.4). It has been suggested that the release of $\text{Ca}^{2+}$ ions is one of two core elements in a general mechanism by which cells respond to external stimuli. The other element is the release of cyclic AMP (Ch. 6, Sec. E.5)^e,j,k.

The primary role in human calcium METABOLISM belongs to Bone tissue. Along with the protein Collagen, the dense bone matrix contains calcium phosphate—a crystalline mineral compound closely related to hydroxyapatite, $\text{Ca}_{10}(\text{PO}_4)_6(\text{OH})_2$. A fraction of the $\text{Ca}^{2+}$ ions is substituted by $\text{Mg}^{2+}$ ions, and a very small fraction of $\text{OH}^-$ ions is replaced by fluoride ions, which enhance bone strength. Embedded within the bone matrix are osteocytes, which include osteoblasts—cells that secrete the substance from which fibrous structures are subsequently built and that promote calcium phosphate deposition. The mineral components of bone tissue are in near chemical equilibrium with calcium and phosphate ions in the blood serum. Bone cells can readily accelerate either the deposition or the dissolution of mineral components in response to local changes in pH, concentrations of $\text{Ca}^{2+}$ or $\text{HPO}_4^{2-}$ ions, and chelating compounds. Large multinucleated cells known as osteoclasts reabsorb calcium.

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Calcium ion Homeostasis is regulated through a complex pathway. Key roles in this process are played by parathyroid hormone (PTH) and the thyroid hormone Calcitonin. When the concentration of $\text{Ca}^{2+}$ ions drops, the secretion of PTH—an 83-amino-acid peptide hormone—increases. Directly under The Influence of this hormone, osteoclasts enhance the dissolution of mineral compounds stored in bones. PTH also increases the reabsorption of $\text{Ca}^{2+}$ ions in the renal tubules. The net effect is an elevation of serum calcium levels. Conversely, when the level of $\text{Ca}^{2+}$ ions rises, the hormone calcitonin is secreted, which acts to lower $\text{Ca}^{2+}$ concentration by accelerating calcium deposition driven by osteoblast activity. Thus, these two Hormones operate via a "push-pull feedback system" (Ch. 6, Sec. E.4). Vitamin D (Appendix 12-G) also participates in regulating calcium ion concentration; it appears to be required for the synthesis of $\text{Ca}^{2+}$-binding proteins necessary for intestinal absorption of $\text{Ca}^{2+}$, its renal reabsorption, and bone dissolution. Timely intake of adequate amounts of vitamin D is a prerequisite for normal calcification processes.

Besides specific $\text{Ca}^{2+}$-binding proteins, $\text{Ca}^{2+}$ ions also bind to several other proteins. These include $\alpha$-amylases (Ch. 7, Sec. B.6), Thermolysin (Ch. 7, Sec. D.4), staphylococcal nuclease (Ch. 7, Sec. E.5), concanavalin A (Fig. 5-7), and certain blood clotting proteins (Fig. 6-16). The latter are of particular interest because they contain specific $\text{Ca}^{2+}-binding sites whose formation depends on vitamin K (Appendix 10-G). Calcium ions also bind to various carbohydrates, such as carrageenan gels (Ch. 2, Sec. B.5).

The concentration of free calcium ions in Tissues is extremely low, and until recently, no reliable method existed for its quantitative assessment. Today, researchers utilize a method based on measuring the intensity of calcium-dependent fluorescence of the protein aequorin (Ch. 13, Sec. 3).

^a Bianchi C. P., Cell $\text{Ca}^{2+}$, Appleton, New York, 1968.

^b Cuthbert A. W., Calcium and Cellular Function, St. Martins, New York, 1970.

^c Zipkin I., ed., Biological Mineralization, Wiley, New York, 1973.

^d Bourne G. H., ed., The Biochemistry and Physiology of Bone, 2nd ed., Vol. 1, Academic Press, New York, 1972.

^e Teo T. S., Wang J. H., JBC, 248, 5950–5955 (1973).

^f Mani R. S., McCubbin W. D., Kay C. M., Biochemistry, 13, 5003–5007 (1974).

^g Rubin R. P., Calcium and the Secretory Process, Plenum, New York, 1974.

^h Siegel F. L., Struct. Bonding (Berlin), 17, 221–268 (1973).

ⁱ Ostwald T. J., MacLennan D. H., JBC, 249, 974–979 (1974).

^j Ostwald T. J., MacLennan D. H., Dorrington K. J., JBC, 249, 5867–5871 (1974).

^k Rasmussen H., Science, 170, 404–412 (1970).

^l McMahon D., Science, 185, 1012–1021 (1974).

ⁿ Dorrington K. J., Hui A., Hofmann T., Hitchman A. J. W., Harrison I. E., JBC, 249, 199—204 (1974).