Biological Chemistry - Berezov T. T., Korovkin B. F. 1998

Hormones
Molecular mechanisms of hormonal signal transduction
Ca2+-messenger system

Ca²⁺ ions play a central role in regulating numerous cellular Functions. Alterations in intracellular free Ca²⁺ concentration act as a signal to activate or inhibit Enzymes, which in turn regulate METABOLISM, contractile and secretory activity, adhesion, and Cell growth. The sources of Ca²⁺ can be both intracellular and extracellular. Under normal conditions, the cytosolic concentration of Ca²⁺ does not exceed 10^-7 M, with the Endoplasmic reticulum and Mitochondria serving as its primary sources. Neurohormonal signals trigger a sharp increase in Ca²⁺ concentration (up to 10^-6 M) coming both from the extracellular space via The Plasma Membrane (specifically through voltage-gated and receptor-gated calcium channels) and from intracellular stores. One of the most critical mechanisms for signal Transduction within the calcium-messenger system is the initiation of cellular responses through the Activation of a specific Ca²⁺-calmodulin-dependent protein kinase. The regulatory subunit of this enzyme has been identified as the Ca²⁺-binding protein calmodulin (molecular mass 17,000). As cellular Ca²⁺ levels rise in response to incoming signals, this specific protein kinase catalyzes the phosphorylation of numerous target intracellular enzymes, thereby modulating their activity. Research has shown that phosphorylase kinase b (activated by Ca²⁺ ions), much like NO synthase, contains calmodulin as a subunit. Calmodulin is also an integral component of many other Ca²⁺-binding Proteins. When calcium levels rise, the binding of Ca²⁺ to calmodulin induces conformational changes, allowing this Ca²⁺-bound form to modulate The activity of a wide array of intracellular proteins (hence its name).

The intracellular messenger system also includes derivatives of Introduction/5.html">Eukaryotic Cell membrane Phospholipids, specifically phosphorylated phosphatidylinositol derivatives. These derivatives are released in response to hormonal signals (such as from vasopressin or thyrotropin) through the action of a specific membrane-bound phospholipase C. Through a cascade of sequential reactions, two potential second messengers are generated: diacylglycerol and Inositol-1,4,5-trisphosphate.

The BIOLOGICAL EFFECTS OF these second messengers are mediated through distinct pathways. The action of diacylglycerol, similar to that of free Ca²⁺ ions, is mediated by protein kinase C—a membrane-bound, Ca²⁺-dependent enzyme that catalyzes the phosphorylation of intracellular enzymes, thereby altering their activity. Inositol-1,4,5-trisphosphate binds to a specific receptor on The endoplasmic reticulum, stimulating the release of Ca²⁺ ions from the reticulum into the Cytosol.

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Thus, the data presented on second messengers indicate that each of these hormone-effect mediator systems corresponds to a specific class of protein Kinases, although a close crosstalk between these systems cannot be ruled out. The activity of type A protein kinases is regulated by cAMP, that of type G protein kinases by cGMP; Ca²⁺-calmodulin-dependent protein kinases are controlled by intracellular [Ca²⁺], while type C protein kinase is regulated by diacylglycerol in synergy with free Ca²⁺ and acidic phospholipids. An elevation in the level of any given second messenger leads to the activation of its corresponding class of protein kinases and the subsequent phosphorylation of their protein substrates. As a result, not only the activity but also the regulatory and catalytic properties of numerous cellular enzyme systems are altered, including Ion Channels, intracellular structural elements, and the genetic apparatus.

It is well established that the effects of Steroid Hormones are mediated through the genetic apparatus by altering Gene Expression. Upon delivery to The Cell via Blood proteins, the hormone diffuses across the plasma membrane and subsequently the nuclear membrane, binding to an intranuclear protein receptor. The steroid-protein complex then binds to the regulatory region of DNA—specifically to hormone-responsive elements—thereby promoting the Transcription of corresponding structural genes, the de novo synthesis of proteins (see Chapter 14), and alterations in cellular metabolism in response to the hormonal signal.

It should be emphasized that the primary and distinguishing feature of the MOLECULAR MECHANISMS OF action between the two Major Classes of hormones is that Peptide Hormones exert their effects predominantly via post-translational (postsynthetic) protein modifications within Cells, whereas steroid hormones (as well as THYROID HORMONES, retinoids, and vitamin D₃ hormones) act primarily as regulators of gene expression. However, this generalization is not absolute, and certain variations exist, as discussed in the context of individual hormones.