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3.1.1.3 Receptors and Signal Transduction at Biomembranes
ОглавлениеApart from ion channels and transporters, there are many other membrane proteins contained in the cytoplasmic membrane, such as receptors, enzymes, and anchor proteins. Some of these are schematically shown in Figure 3.5a.
In a multicellular organism, the cells must be able to recognize and process signals from outside, coming from other cells or tissues. There are several cellular communication options (Figure 3.7):
Endocrine signals (hormones) are produced by endocrinal gland cells (Table 3.2) and are released into the bloodstream. They circulate through the body and are picked up by receptors in the target cells – sometimes in a very distant part of the body – where they spring into action. In other words, hormones have a systemic effect. Hydrophilic and polar hormones (adrenaline and growth factors) bind to cell surface receptors, whereas lipophilic hormones (e.g. steroidal hormones, thyroxine, retinoic acid, vitamin D3) diffuse into the target cells to bind to intracellular receptors. These act as transcription regulators, controlling the expression of hormone‐regulated genes.Paracrine signals have an effect on their immediate surroundings. Released from a tissue cell, they are recognized and processed by neighboring cells. Their effect is local (e.g. prostaglandins).In direct cell‐to‐cell interaction, a cell presents a membrane‐bound signaling molecule to another cell carrying a membrane receptor that recognizes the molecule. Examples are found in the immune system (e.g. MHC complex and T‐cell receptors).In neuronal signal transduction, an electric signal (action potential) is transformed into a chemical signal at the synapse. Neurotransmitters are released that are recognized and processed by the receptors of a postsynaptic target cell.
Figure 3.7 Schematic view of communication pathways between cells. (a) Endocrine signaling. (b) Paracrine signaling. (c) Synaptic signaling. (d) Contact‐dependent signaling.
Source: Alberts et al. (2015). Adapted with permission of Garland Science.
Table 3.2 Most important hormones in humans.
| Hormone | Hormone gland | Target | Activity/function |
|---|---|---|---|
| Releasing hormones (P) | Hypothalamus | Adenohypophysis | Regulate release of hormones from adenohypophysis |
| Inhibitory hormones (P) | Hypothalamus | Adenohypophysis | Regulate release of hormones from adenohypophysis |
| Oxytocin (P) | Hypothalamus | Uterus, mammary gland | Stored and released from neurohypophysis; stimulates uterus contractions, milk secretion, love, and empathy |
| Thyreotropin (GP) | Adenohypophysis | Thyroid | Stimulates synthesis and secretion of thyroxin |
| Adrenocorticotropic hormone (ACTH) (P) | Adenohypophysis | Adrenal cortex | Stimulates secretion of hormones of adrenal cortex |
| Luteinizing hormone (LH) (GP) | Adenohypophysis | Gonads | Stimulates secretion of sex hormones from ovary and testes |
| Follicle‐stimulating hormone (FSH) (GP) | Adenohypophysis | Gonads | Stimulates development of egg and sperm cells |
| Somatotropin (hGH) (P) | Adenohypophysis | Bones, liver, muscles | Stimulates protein synthesis and growth |
| Prolactin (P) | Adenohypophysis | Mammary | Stimulates milk production |
| Melanocyte stimulating hormone (MSH) (GP) | Adenohypophysis | Melanocytes | Regulates pigmentation of skin |
| Endorphins, enkephalins (P) | Adenohypophysis | Neurons of spinal cord | Analgesic properties |
| Adiuretin (ADH, vasopressin) (P) | Neurohypophysis | Kidneys | Stimulates water reabsorption and increases blood pressure |
| Melatonin (AA) | Epiphysis | Hypothalamus | Regulates biological rhythms (e.g. day/night rhythm) |
| Thyroxin (AA) | Thyroid | Many tissues | General stimulant of metabolism |
| Calcitonin (P) | Thyroid | Bones | Stimulates bone formation, lowers Ca2+ levels in blood |
| Parathormone (P) | Parathyroid | Bones | Stimulates bone absorption, increases Ca2+ levels in blood |
| Thymosins (P) | Thymus | Leukocytes | Activates T‐cell activity |
| Glucagon (P) | Pancreas | Liver | Stimulates glycogen breakdown, increases blood sugar levels |
| Somatostatin (P) | Pancreas | Pancreas | Inhibits release of glucagon, insulin, and digestive enzymes |
| Insulin (P) | Pancreas | Liver, muscles | Stimulates uptake of glucose and glycogen formation |
| Gastrin (P) | Stomach | Stomach | Stimulates release of digestive juices, enhances motility of stomach |
| Secretin (P) | Duodenum | Pancreas, stomach, gall bladder | Regulates digestion processes, induces contraction of gall bladder |
| Adrenaline/noradrenaline (AA) | Adrenal medulla | Heart, liver, blood vessels | Stimulates glycogen breakdown; stimulate heart, circulation, and blood pressure |
| Cortisol (glucocorticoid) (S) | Adrenal cortex | Muscles, many tissues | Regulates stress reactions, stimulates metabolism of proteins and lipids, undergoes gluconeogenesis, inhibits inflammatory reactions |
| Aldosterone (mineral corticoid) (S) | Adrenal cortex | Kidneys | Stimulates excretion of K+ and ammonium ions and Na+ reabsorption |
| Estrogen (S) | Ovary | Mammary, uterus | Regulates development and function of female sexual characters and sexual behavior |
| Progesterone (gestagen) (S) | Ovary (corpus luteum) | Uterus | Important for pregnancy and embryonic development |
| Testosterone (S) | Testes | Diverse tissues | Regulates formation of sperm cells, development and function of male sexual characters and sexual behavior; can enhance aggressiveness |
| Atrial natriuretic peptide (ANP) (P) | Heart | Kidneys | Stimulates Na+ excretion |
| Vitamin D (S) | Skin | Bones, kidneys | Enhances blood Ca2+ level |
P, peptide or protein; S steroid; GP, glycoprotein; AA, amino acid derivative.
Polar signaling molecules that are unable to pass the biomembrane through diffusion are recognized by receptors on the cell surface. There are three categories of such receptors (Figure 3.8):
Ion channel‐linked receptors are activated by specific ligands. As a reaction, the conformation of the channel protein is modified, leading to the opening or closure of the channel in question. Ions are let in or out accordingly. The changes in ion concentration produce a change in the membrane potential. In this way, the tension in ion channels can be regulated, or new action potentials released. Ion channel‐linked receptors are mainly found in the neuronal system, such as the nicotinic acetylcholine receptor(nAChR), the GABA receptor, the NMDA receptor, and the glycine receptor.
G‐protein‐coupled receptors (GPCRs) communicate with a G‐protein that is bound either to GTP or GDP. The activation of this type of receptor by a ligand causes a conformation change, which is recognized by the G‐protein. The G‐protein (or, to be more precise, its α‐subunit) is activated and can, in turn, interact with a membrane‐bound effector protein. The effector protein is often an enzyme (adenylyl cyclase or phospholipase), which produces second messengers. This mechanism whereby a single signaling molecule activates a multitude of effector proteins, which, in turn, release a host of second messengers, results in an effective amplification of the signal. Adenylyl cyclase turns ATP into cAMP, which acts as second messenger, regulating protein kinase A allosterically. Once protein kinase A has been activated, it may phosphorylate other enzymes or proteins (e.g. transcription factors), which then spring into action (Figure 3.9). After the dissociation of the α‐subunit, the βγ‐complexes of the activated G‐protein can also be biologically active. In the cardiac muscle, acetylcholine binds to a muscarinic receptor(mAChR), thus activating the βγ‐complex. The βγ‐complex binds to K+ channels and opens them. cAMP is degraded by phosphodiesterase – an enzyme that is considered a target structure for several pharmaceutical products (e.g. caffeine). Table 3.3 gives an overview of some essential hormones that are amplified by adenylyl cyclase and cAMP. A few signal system use cGMP instead of cAMP (e.g. in photoreceptors).
Figure 3.8 Schematic representation of receptor classes on the cell surface. (a) Ion channel‐coupled receptors. (b) G‐protein‐coupled receptors. (c) Enzyme‐coupled receptors (e.g. the tyrosine kinases).
Source: Alberts et al. (2015). Adapted with permission of Garland Science.
Figure 3.9 Activation of adenylyl cyclase and formation from cAMP as second messenger.
Source: Alberts et al. (2015). Adapted with permission of Garland Science.
Table 3.3 The role of adenylyl cyclase and phospholipase C‐β in signal transduction.
| Signaling molecule | Target tissue | Main reaction |
|---|---|---|
| Adenylyl cyclase | ||
| Adrenaline | Heart | Raising heart frequency and enhancing contraction, muscles, glycogen degradation |
| Muscle | Breakdown of glycogen | |
| ACTH | Adrenal gland (cortex) | Secretion of cortisone |
| ACTH, adrenaline | Fat tissue | Breakdown of triglycerides |
| Glucagon | Liver | Glycogen degradation, increase of blood glucose levels |
| Parathormone | Bone | Bone resorption |
| Vasopressin | Kidney | Water resorption |
| Luteinizing hormone | Ovary | Progesterone secretion |
| Thyroid‐stimulating hormone (TSH) | Thyroid gland | Synthesis and release of thyroid hormone |
| Phospholipase C‐β | ||
| Vasopressin | Liver | Glycogen degradation |
| Acetylcholine | Pancreas | Secretion of amylase |
| Smooth muscles | Muscle contraction | |
| Thrombin | Platelets | Platelet aggregation |
Four families of trimeric G‐proteinshave been discovered, which are active in a diversity of signaling pathways (Table 3.4). Few G‐proteins directly regulate elements of the cytoskeleton or ion channels:
Phospholipase C is another important effector protein, cleaving phosphatidylinositol into inositol‐1,4,5‐triphosphate (IP3) and diacylglycerol(DAG) after activation (Figure 3.10). IP3 acts as second messenger, binding to ryanodine receptors in the ER and thus activating a calcium channel. Calcium can also act as a signaling substance, activating, for example, protein kinase C(PKC), various calmodulin(CaM)‐dependent kinases, and many other proteins (Figure 3.11). PKC, a modulator of many target proteins (such as transcription factors), can also be activated by DAG (Figure 3.11). Table 3.3 summarizes the major signaling processes involving phospholipase C‐β. For medical research, G‐protein‐linked signaling pathways are of major interest, as they are used by many currently available pharmaceuticals. There are still many unknown steps in the process, which could prove interesting targets for new drugs to be developed.
Enzyme‐linked receptors can be activated by a signaling molecule (e.g. various growth factors that stimulate cell division) (Figures 3.8 and 3.11). In dimeric receptors, two units form an active receptor with enzyme domains on the cytosolic side. The dimerization process activates tyrosine kinases (Table 3.5) that begin to phosphorylate each other. They are termed receptor tyrosine kinase (RTK). The phosphotyrosine residues are recognized by specific adapter proteins that are activated by them and then cause the activation of other signaling proteins (Figure 3.11). Proteins of the Ras superfamily (monomeric GTPases) mediate signaling in most RTKs. Since such enzyme‐linked receptors are often found in tumor cells where they are overexpressed or permanently activated, their inhibition, especially the inhibition of tyrosine kinase, is a major strategy in the treatment of cancer. The drug Gleevec (STI‐571) binds to the ATP‐binding site and thus inhibits tyrosine kinases effectively.
Nitric oxide is a gaseous signaling mediator with many functions. It is being synthesized from arginine by NO synthases(NOS). In smooth muscles, e.g. those of the endothelium of blood vessels, NO induces a relaxation. NO activates guanylyl cyclase, leading to cGMP formation, which lead to the relaxation of smooth muscles.
Table 3.4 Some functions of trimeric G‐proteins.
| Family | Family members | Effective subunit | Some functions |
|---|---|---|---|
| I | Gs | α | Activates adenylyl cyclase and Ca2+ channels |
| Golf | α | Activates adenylyl cyclase in olfactory neurons | |
| II | Gi | α | Inhibits adenylyl cyclase |
| βγ | Activates K+ channels | ||
| Go | βγ | Activates K+ channels, inactivates Ca2+ channels | |
| Gt | α | Activates cGMP phosphodiesterase in photoreceptors | |
| III | Gq | α | Activates phospholipase C‐β |
| IV | G12/13 | α | Activates Rho GTPases to regulate the actin cytoskeleton |
Source: Alberts et al. (2015). Reproduced with permission of Garland Science.
Figure 3.10 Role of phospholipase C‐β in the production of second messengers IP3 and DAG.
Source: Alberts et al. (2015). Adapted with permission of Garland Science.
Figure 3.11 Signal transduction after activation of G‐protein and enzyme‐linked receptors. GPCR, G‐protein‐coupled receptor; GEF, guanine exchange factor.
Source: Alberts et al. (2015). Adapted with permission of Garland Science.
Table 3.5 Signal proteins that act via receptor tyrosine kinases.
| Signal protein | Receptor | Activity |
|---|---|---|
| Epidermal growth factor | EGF‐R | Stimulates cell growth and differentiation |
| Insulin | Insulin‐R | Enhances glucose consumption and protein synthesis |
| Insulin‐like growth factor | IGF‐1‐R | Stimulates cell growth and survival in many cell types |
| Nerve growth factor (NGF) | Trk R | Stimulates cell growth and survival of neurons |
| Platelet‐derived growth factor (PDGF) | PDGF‐R | Stimulates cell growth, differentiation and cell migration |
| Macrophage colony‐stimulating factor (MCSF) | MCSF‐R | Stimulates cell growth and differentiation of macrophages and monocytes |
| Fibroblast growth factors (FGF1–FGF24) | FGF‐R | Stimulates cell growth and differentiation |
| Vascular endothelial growth factor (VEGF) | VEGF‐R | Stimulates angiogenesis |
| Ephrin | Eph‐R | Stimulates angiogenesis and axon orientation |
R, receptor.
These signal pathways have in common that they amplify the original signal from a few signal molecules to thousands of second messengers (cAMP, Ca2+), which can trigger thousands of targets (Figure 3.11). The pathways downstream the original receptor are often not linear but complex networks. Members of pathways and networks often assume roles in more than a single context, which make their analysis far from easy. Many elements of these pathways behave like molecular switches, which can quickly change their state from active to inactive. Reversible phosphorylation/dephosphorylation and binding of GTP/GDP or ATP/ADP are common elements of these switches (Figure 2.16). Many pathways and networks are apparently regulated by positive and negative feedback mechanism.
