Biological Membranes - A. N. Ogurtsov 2012

Electrogenesis of Biomembranes
Membrane Receptors
Types of Membrane Receptors

Single-celled organisms gather information from their environment, typically in the form of light or chemical signals, which can be represented by A wide variety of chemical compounds.

If a unicellular Organism is capable of independent movement, the signals that attract it are called attractants, and in this case, The Cell will move toward regions of increasing attractant concentration. Conversely, repellent substances prompt the unicellular organism to move away toward lower signal concentrations.

In Multicellular Organisms, two levels of signal perception and Transduction are distinguished.

1. The organism level as a whole, which receives environmental information through Sensory Organs such as eyes, ears, etc. This is referred to as sensory reception, which mediates the perception of wave energy (light, sound, heat) and, in the case of Olfaction and Taste, chemical signals.

2. The level of cell-cell communication within a multicellular organism. Cells exchange information primarily through the language of chemical signals, represented by various primary messengers, including Hormones, Neurotransmitters, and certain protein factors other than hormones.

Metaphorically speaking, cells possess a "team spirit"—their behavior can depend on the presence of neighbors and be regulated via intercellular interactions; such effects are also mediated by receptors integrated into the outer cell membrane. When comparing single- and multicellular organisms in terms of The complexity of their intracellular metabolic pathways, it turns out that the difference between them is not all that striking.

According to paleontological data, single-celled organisms comparable in Organization level to modern Bacteria appeared approximately 3.5 billion years ago. However, the first multicellular organisms emerged only a billion years later. It can be hypothesized that this billion-year span was precisely what was required to integrate unicellular organisms with already well-established metabolisms into a multicellular community.

For a multicellular organism to arise and subsequently thrive, individual cells had to learn to coordinate their activities so that their METABOLISM, proliferation and death, localization within a particular organ or tissue, and other Functions and characteristics were subordinated primarily to the interests of the entire cellular community.

As a result, a healthy cellular community—such as a multicellular organism—maintains harmony among its members, specifically achieving a precise balance between cell proliferation and programmed cell death, or apoptosis.

If the control over these opposing processes is disrupted, excessive apoptosis leads to tissue degeneration; conversely, if cellular individualism prevails and runaway cell proliferation ensues, tumor growth and Cancer develop, ultimately resulting in the death of both the organism and the rogue cancer cells originating from it.

Levels of Regulation of the cellular response. Generally speaking, three main levels of cellular response regulation can be distinguished.

1. Transcriptional level. At this stage, regulation can affect Transcription itself, subsequent Processing of the mRNA precursor, as well as the degradation of both the precursor and the mRNA molecule.

2. Translational level. Regulation may target Protein Synthesis itself, its subsequent modification, or the degradation rate of pre-mRNA or the protein molecule itself.

3. Protein level. Regulation operating at the level of mature Proteins, carried out through the four mechanisms listed below.

Four mechanisms of cellular response Regulation at the protein level.

1. Reversible Covalent Modification of proteins. An example is the phosphorylation of Glycogen phosphorylase, catalyzed by a specific protein kinase. The reverse process of protein dephosphorylation is catalyzed by protein Phosphatases. Both of these opposing processes (phosphorylation/dephosphorylation) are widely utilized by cells to alter The properties of diverse proteins through covalent modification. Another important mechanism involves the covalent attachment of hydrophobic groups—methyl and certain acyl groups, such as palmitic acid residues—to Polypeptides.

2. Alteration of catalytic activity and other protein properties by ligands. The number of such ligands is vast, but secondary messengers are the most critical for signaling systems: cAMP, cGMP, DAG, IP₃, and Ca²⁺ ions. Each of these can regulate The activity of specific protein Kinases and, consequently, the phosphorylation level of their respective target proteins.

3. Modulation of protein properties via Protein-Structure/156.html">Protein Interactions. An example is the cAMP-dependent protein kinase (protein kinase A) (see [1] sections 6.6.4, 6.8.1) (Figure 146).

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Figure 146 - cAMP-induced activation of protein kinase A

This enzyme molecule, consisting of two catalytic (C) and two regulatory (R) subunits, is inactive because each regulatory subunit within the tetramer acts as an inhibitor of the catalytic components' protein kinase activity. However, in the presence of cAMP, the tetramer dissociates into its constituent parts, freeing the catalytic subunits from inhibition so they can phosphorylate target proteins.

4. Alteration of compartmentalization. Changes in compartmentalization (or subcellular localization) of a protein molecule—for instance, its translocation from the Cytosol (one compartment) to the membrane (another compartment)—can trigger dramatic alterations in protein properties that are essential for their signaling functions. Perhaps one of the most striking Examples is the widespread protein p21^ras, which is directly implicated in the malignant transformation of Human and Animal cells. More precisely, this applies to mutant forms of p21^ras, whereas its normal counterpart participates in signaling pathways where protein growth factors serve as primary messengers regulating Cell Division and differentiation. It has recently been established that upon receiving a signal from the appropriate receptor, p21^ras shifts into an activated state, and its subsequent task is simply to translocate a specific protein kinase known as Raf from the Cytoplasm to the membrane.

Regulation at the level of mature Proteins can also occur through other pathways, such as secretion, exocytosis, and endocytosis.

MAIN TYPES OF Membrane Receptors. There are three Major Types of receptors integrated into the outer cell membrane:

1) G protein-coupled receptors (GPCRs);

2) ion channel-coupled receptors;

3) enzyme-linked receptors.

G-protein coupled receptors (GPCRs) transmit signals from primary messengers to intracellular targets via the GPCR→G protein→effector protein cascade. A wide variety of molecules serve as primary signals for these receptors, such as low-molecular-weight hormones and neurotransmitters (e.g., adrenaline, noradrenaline, acetylcholine, serotonin, histamine), opioids, Peptide and Protein hormones (adrenocorticotropin, Somatostatin, vasopressin, angiotensin, gonadotropin, epidermal growth factor), and certain Neuropeptides.

This group also includes numerous chemical signals perceived by olfactory and taste sensory cells, as well as light, the receptor for which is the visual pigment rhodopsin found in photoreceptor cells.

It should be noted that the same primary signal can initiate signal transduction through several (sometimes more than 10) different GPCRs; thus, while the number of external signals for GPCRs is several dozen, over 200 such receptors are known.

Despite their diversity, GPCRs are monomeric integral Membrane Proteins whose polypeptide chain spans The cell membrane seven times. In all cases, the region of the receptor responsible for interacting with the primary signal is localized on the extracellular side of the membrane, whereas the region contacting the G protein is on its cytoplasmic side.

The next component of the GPCR-mediated signal transduction cascade is the G protein. About 20 different G proteins have been identified; among them, the most notable are G_s and G_i, which respectively stimulate and inhibit adenylate cyclase; G_q, which activates phospholipase C; and G proteins of sensory cells: photoreceptor G_t (Transducin), olfactory G_olf, and gustatory G_g.

G proteins are heterotrimers consisting of Three types of subunits: α, β, and γ, although under physiological conditions the latter two subunits function as a single βγ-complex. A critical feature of G proteins is the presence of a guanine nucleotide-binding site—for GDP and GTP—on their α-subunit (Figures 139, 145). Binding to GTP corresponds to the activated state of the G protein, whereas the presence of GDP in the nucleotide-binding site corresponds to the inactive state (Figure 79).

The central event in signal transmission from the receptor—activated by a primary signal—to the G protein is that the activated receptor catalyzes the exchange of GDP bound to the G protein for GTP present in the medium. This GDP/GTP exchange on the G protein is accompanied by the dissociation of the trimeric G protein molecule into two functional subunits: the GTP-containing α-subunit and the βγ-complex (Figures 139, 145).

Next, one of these functional subunits (depending on the type of signaling system) interacts with an effector protein, which is typically an enzyme or an ion channel. As a result, their catalytic activity or ion conductance changes accordingly, which in turn alters the cytoplasmic concentration of The secondary messenger (or ion) and ultimately triggers a specific cellular response.

Effector proteins in GPCR→G protein→effector protein signaling systems can include adenylate cyclase, which catalyzes the synthesis of cAMP from ATP; phospholipase C, which hydrolyzes phosphatidylinositol to form DAG and IP₃; phosphodiesterase, which cleaves cGMP to GMP; and certain types of potassium and calcium channels.

Importantly, during signal transmission along the receptor→G protein→effector protein cascade, the initial external signal can be repeatedly amplified. This occurs because a single receptor molecule, during its activated state (R*), manages to convert several G protein molecules into their active form (G*).

For instance, in the rhodopsin→G→cGMP phosphodiesterase visual cascade, several hundred or even thousands of G_t* molecules can be produced per R* molecule, meaning that the external signal Amplification factor at The First stage of the cascade (R*→G*) is 10²–10³. Although at the next stage of the cascade (G*→effector protein) each G* molecule interacts with only a single effector protein molecule, the signal is still amplified here because numerous secondary messenger molecules appear (or disappear) in the cytoplasm for every G* molecule and, consequently, each activated effector protein molecule. Thus, in the visual cascade, at its Second Stage, a single activated cGMP phosphodiesterase molecule is capable of hydrolyzing up to 3,000 molecules per second of cGMP, which serves as a secondary messenger in photoreceptor cells.

The overall amplification factor of the cascade equals the product of the amplification factors at all its stages. The signal amplification factor as it passes through the cascade can reach very high values: in visual cells, this is on the order of 10⁵–10⁶.

The cessation of an external stimulus is accompanied by the shutdown of all Components of the signaling system. At the receptor level, this is achieved, firstly, through the dissociation of the primary messenger from the GPCR complex, and secondly, by phosphorylation of the receptors via special protein kinases followed by the binding of a specific protein (e.g., β-arrestin) to the modified receptor.

G proteins possess GTPase activity—that is, The ability to hydrolyze their bound GTP to GDP, which ensures their self-inactivation, or the transition G-GTP→G-GDP. Because the activation state of the effector protein (on/off) directly depends on the state of the G protein, this transition also results in the deactivation of the effector protein, and consequently, the cessation of secondary messenger synthesis (or Hydrolysis) or the closure of the ion channel.

Finally, for the cell to fully return to its resting state (prior to the external stimulus), specialized mechanisms restore the baseline levels of the secondary messenger or cation in the cytoplasm. For example, cAMP, whose cytoplasmic concentration increases during signal transduction via the β-adrenergic receptor→Gs protein→adenylate cyclase cascade, is subsequently hydrolyzed by cAMP phosphodiesterase into non-cyclic (linear) AMP, which lacks secondary messenger properties.

Ion channel-coupled receptors. Ion channel-coupled receptors function simultaneously as Ion Channels and as receptors capable of specifically binding primary signals from the extracellular side, thereby altering their ion conductance (cationic or anionic, depending on the receptor type).

Receptors of this type utilize certain neurotransmitters responsible for synaptic transmission in electrically excitable cells as primary signals. Classic examples of this include cationic nicotinic acetylcholine receptors located on the membrane of Skeletal Muscle cells at their synapses with motor Neurons (see section 16.5), as well as similar receptors found in the electric organs of rays.

Enzyme-linked receptors vary widely in their quaternary (subunit) structure. With few exceptions, they are either monomers that dimerize upon binding a primary messenger, or oligomers formed by several subunits of different types. In virtually all of these receptors, the polypeptide chain of their monomeric subunits crosses the cell membrane only once. They also share the feature that the primary signal-binding site is localized on the extracellular side of the receptor.

Based on their mechanism of interaction with cytoplasmic targets, receptors of this type are divided into two groups.

The first group comprises enzyme-linked receptors that feature a catalytic domain on their cytoplasmic side, which is activated upon the action of an external signal on the receptor.

Let us outline the main types of enzyme-linked receptors.

First, mention should be made of the extensive family of receptor protein-Tyrosine kinases capable of autophosphorylation (see section 15.2)—that is, phosphorylating themselves at tyrosine residues as well as phosphorylating tyrosine residues on target proteins.

Second, these are receptors possessing protein-tyrosine phosphatase activity, which dephosphorylate phosphotyrosine residues on target proteins. It is worth noting that receptor protein-tyrosine kinases and protein-tyrosine phosphatases are involved in regulating such critical events as cell division, differentiation, and the Immune Response.

Third, there are Receptor guanylyl cyclases that catalyze the Synthesis of the secondary messenger, cGMP, from GTP. Receptors of this type are involved in the Regulation of Water-salt balance and vascular tone.

The second group of receptors under consideration lacks intrinsic enzymatic activity. However, in the presence of an external signal, they acquire the ability to bind cytoplasmic (non-receptor) protein tyrosine kinases, which are inactive in their free state but become activated upon complexation with the receptor and phosphorylate it (see Section 15.3). The incorporation of phosphate residues into such a receptor-anchor creates conditions for the binding of other target proteins, which are also phosphorylated and thereby transmit the signal downstream. This group includes receptors involved in The Development of the immune response, specifically antigen receptors and cytokine or interleukin receptors.

Some mechanisms of membrane reception will be discussed in more detail below.