L6 Biophysics BMS131 Physiology Lec6 Fall 2024 PDF

# Intercellular Communication and Signal Transduction ## Biophysics - Physiology Lecture 6 **Prof. Sahar El Agaty | Professor of Physiology** **Powered by: Arizona State University** ## Intended Learning Outcomes - Recognize different mechanisms of intercellular communication. - Discuss the mech...

# Intercellular Communication and Signal Transduction ## Biophysics - Physiology Lecture 6 **Prof. Sahar El Agaty | Professor of Physiology** **Powered by: Arizona State University** ## Intended Learning Outcomes - Recognize different mechanisms of intercellular communication. - Discuss the mechanism by which ligand gated receptor channels, and receptor-enzyme complex can affect the cell activity. - Give an account on G-protein coupled receptors. - Summarize the types of second messenger. ## Intercellular Communication **Regulation of many activities of cells throughout the body to maintain life depends on the ability of cells to communicate with one another.** **Intercellular communication can take place either directly or indirectly.** ### Direct intercellular communication - It involves physical contact between the interacting cells. - **Types:** #### Gap junctions: - They are tunnels that bridge the cytoplasm of neighboring cells. - Through gap junctions, ions and small molecules are directly exchanged between closely associated interacting cells without ever entering the ECF. #### Transient direct link of surface markers: - Some cells, such as those of the immune system, have specialized markers on the surface membrane that allow them to directly link with certain other cells that have compatible markers for transient interactions. For example, white blood cells recognize and selectively destroy bacteria, viruses, and cancer cells. ### Indirect intercellular communication: - It occurs through chemical messengers, or signal molecules - **Types of chemical messenger:** #### Paracrines/autocrines: - Paracrines are local chemical messengers, produced by cells and exert their effect on neighboring cells. - **Characteristics:** - Because paracrines are distributed by simple diffusion within the interstitial fluid, their action is restricted to short distances. - They do not gain entry to the blood because they are rapidly inactivated by locally existing enzymes. - For example: Histamine which is released by connective tissue cell (mast cell) during inflammation within injured or invaded tissue and causes vasodilatation, bringing white blood cells to affected area. - Autocrines act on cells that secrete it. **Neurotransmitters:** - Neurons communicate with the cells they innervate (their target cells e.g., neuron, muscle or gland) by releasing neurotransmitters, which are short-range chemical messengers, in response to electrical signals (action potentials). - Neurotransmitters diffuse from their site of release across a narrow extracellular space to act locally on specific receptors on target cells. #### Hormones are long-range chemical messengers specifically secreted into the blood by endocrine glands. - The blood carries the messengers to other sites in the body, where they exert their effects on their target cells some distance from their site of release - Only the target cells of a particular hormone have membrane receptors for binding with this hormone. - Nontarget cells are not affected by any blood-borne hormones that reach them. #### Neurohormones: - Neurohormones are hormones released into the blood by neurons. - An example is vasopressin, a neurohormone produced by nerve cells in the brain that increases water conservation by the kidneys during urine formation. Also, Oxytocin a neurohormone produced by nerve cells in the brain that increases uterine contraction. - **The chemical nature of chemical messenger:** - The chemical messengers include: - Amino acids - Steroids - Polypeptides - Sometimes, lipids, purine nucleotides, and pyrimidine nucleotides. - **N.B.** In various parts of the body, the same chemical messenger can function as a neurotransmitter, a paracrine mediator, a hormone secreted by neurons into the blood (neural hormone), and a hormone secreted by gland cells into the blood. ## Signal Transduction **Definition:** - It is the process by which the chemical messenger coming to the target cell performs a specific change in intracellular activity (response). - Signal transduction occurs by different mechanisms, depending on a) the chemical messenger and b) the receptor type. ### Chemical Messenger #### Lipid-soluble chemical messengers: - For example: Steroid hormones (glucocorticoids, estrogen, progesterone, and testosterone), and 1,25-dihydroxycholecalciferol (active Vitamin D3). - They can cross cell membrane and act on cytoplasmic receptors (intracellular receptors). - This binding **changes gene activity (transcription)**, either turning on or suppressing transcription of specific genes. - In this way the messenger controls the level of activity of the transcribed protein, such as an enzyme. - Thyroxine act on nuclear receptor and also changes gene activity. #### Water-soluble extracellular chemical messengers: - They cannot cross the plasma membrane such as: - Peptide (protein) hormones delivered by the blood - Neurotransmitters released from nerve endings - Paracrines released locally. - They bind to specific receptor on the surface of cell membrane. - This binding causes a sequence of intracellular events that controls a particular cellular activity, such as membrane transport, secretion, metabolism, or contraction. - They are known as first messengers. - The water soluble chemical messenger act on the following receptors: - Ligand-gated receptor-channel - Receptor-enzyme complex - G-protein-coupled receptor ### Ligand-gated receptor-channel: - Messenger binding to a ligand-gated receptor-channel opens or closes the channel, with the resultant ion movement leading to the cell's response. - In this case, the receptor itself serves as an ion channel. - When the chemical messenger binds to the receptor channel, the channel opens or closes. - For example: acetylcholine binds to nicotinic receptors which are ligand gated channels results in opening of these channels and increases Na+ influx. ### Receptor-enzymes complex: - Messenger binding to a receptor-enzyme complex activates tyrosine kinase, which phosphorylates specific proteins that lead to the cell's response. - The receptor enzyme has portion facing ECF and a tyrosine kinase site on cytoplasmic portion. - Binding of chemical messenger on ECF portion → phosphorylation of tyrosine on cytoplasmic portion of the receptor enzyme → Designated protein binds to the receptor enzyme and is phosphorylated → change shape and function of the designated proteins (are activated). - Example: Insulin, growth hormone, prolactin and nerve growth factor. ### G-protein-coupled receptors (activation of Second-messenger pathway): - The receptor is coupled with an intracellular regulatory protein that are activated after binding of GTP (G-proteins). - It is also called G-protein-coupled receptor (GPCR). - When an activating signal reaches a G-protein, the protein exchanges GDP for GTP. The GTP-protein complex brings about the activating effect of the G-protein. - Messenger (first messenger)binding to a G-protein-coupled receptor causes the release of intracellular mediators (second messenger) such as cAMP, inositol trisphosphate (IP3), and diacylglycerol DAG that carry out the cell's response. - Binding of the first messenger to the receptor activates the G protein→ change the activity of nearby protein called effector protein → increased concentration of a second messenger which causes series of chemical reaction that produce a change in the shape and function of designated proteins - The intracellular pathways activated by a second messenger are similar among different cells despite the variation of responses. - The variability in response depends on the specialization of the cell, not on the mechanism used. - About half of all drugs prescribed today act on G-protein-coupled receptors. - The effects of protein kinases in signal transduction pathways are reversed by another group of enzymes called **protein phosphatases**, which dephosphorylate the specific protein. - Protein phosphorylation/dephosphorylation plays a central role in regulating the activity of proteins and thus their extensive roles in cellular physiology. - Second messengers may be cAMP, inositol trisphosphate (IP3), and diacylglycerol DAG that carry out the cell's response. ### Cyclic AMP Second-Messenger Pathway: - Cyclic AMP is the most widely used second messenger. - Binding of chemical messenger to its receptor→ activates the associated protein G → activates the effector protein-in this case, the enzyme **adenylyl cyclase**. - Adenylyl cyclase converts intracellular ATP to cAMP. - The second messenger cAMP activates protein kinase A → phosphorylates a designated preexisting intracellular protein, such as an enzyme important in a particular metabolic pathway. - Phosphorylation causes the protein to change its shape and function, thus activating it. - This regulates a specific metabolic event may be increased or decreased. **For Example:** - Catecholamines on Beta receptors - Glucagon - Parathyroid hormone - Follicle-stimulating hormone (FSH) - Vasopressin (V2 receptor, epithelial cells on kidney) - Different types of cells have different designated proteins available for phosphorylation and modification by protein kinase A (PKА). - CAMP can cause different responses in different cells, ["turn on" or "turn off] depending on a) what proteins are modified, and b) the kind target cells - For example, depending on its cellular location, activating the cAMP pathway can: - change heart rate in the heart. - stimulate the formation of female sex hormones in the ovaries - break down stored glucose in the liver - control water conservation during urine formation in the kidneys. ### Inositol trisphosphate (IP3), and diacylglycerol DAG: - Binding of the first messenger to the G-protein coupled receptor leads to G proteins activation of the enzyme **phospholipase C**, an effector protein bound to the inner side of the membrane. - This enzyme breaks down **phosphatidylinositol bisphosphate (PIP2)**, a component of the phospholipid molecules within the membrane itself. - The products of PIP2 breakdown are **diacylglycerol (DAG)** and **inositol trisphosphate (IP3)**. - IP3 and DAG themselves are considered to be second messengers. #### Inositol trisphosphate (IP3): - IP3 diffuses into the cytoplasm and mobilizes intracellular Ca2+ stored in the endoplasmic reticulum (ER) to increase cytosolic Ca2+ by binding with IP3-gated receptor-channels in the ER membrane. #### Diacylglycerol (DAG): - DAG, sets off another second-messenger pathway. - DAG activates **protein kinase C (PKC)**, which phosphorylates designated proteins, different from those phosphorylated by calmodulin. - The resultant change in shape and function of these proteins activates them. - Also, DAG activates receptor-operated Ca2+ channels in the plasma membrane to further increase intracellular Ca2+ concentration - Calcium binds to calmodulin (intracellular protein) - The Ca2+-calmodulin complex activates Ca2+-calmodulin dependent protein kinase (CaM kinase) - The activated CaM kinase phosphorylates the designated proteins. - For example, the Ca2+-calmodulin pathway is the means by which chemical messengers can activate smooth muscle contraction. **For Example:** - Angiotensin II (vascular smooth muscle) - Catecholamines (a receptors) - Oxytocin - Vasopressin (V1 receptor, vascular smooth muscle) ### GuanyLyl cyclase - Guanylyl cyclases are a family of enzymes that catalyze the formation of cyclic guanosine monophosphate (cyclic GMP or cGMP). - cGMP is important in vision in both rod and cone cells. - In addition, there are cGMP-regulated ion channels, and cGMP activates cGMP-dependent kinase, producing a number of physiologic effects. - For example: atrial natriuretic peptide (ANP) and nitric oxide (NO). ## Receptors ### Intracellular: - Cytoplasmic - Nuclear ### Extracellular: - Ligand-gated receptor-channel - Receptor-enzyme complex - G-protein-coupled receptor - Receptor number increases and decreases in response to various stimuli. - ↑↑ Chemical messenger → The number of active receptors generally decreases (downregulation). - Chemical messenger ↑↑ The number of active receptors (upregulation). ## Clinical Note: - Receptors participate in some way in most body functions, so they are important targets for a variety of drugs used to treat many disorders. - **For example:** - B2 adrenergic receptor agonist are used in bronchial asthma. - Histamine-1 receptor (H1-receptor) antagonists are used to decrease allergic reactions. - Histamine-2 receptor (H2-receptor) antagonists: treating excess stomach acid. - **Receptor & Diseases** - Certain diseases are caused by production of antibodies against receptors. - **For example:** - Antibodies against thyroid-stimulating hormone (TSH) receptors cause Graves disease. - Antibodies against nicotinic acetylcholine receptors cause myasthenia gravis. ## Student Activity: - True and false - Paracrines actions extend for long distance. **F** - Nicotinic receptors of acetylcholine ar G-Protein coupled receptors **F** - Increased chemical messenger is associated with downregulation of its receptors. **T** ## References: 1. Barrett KE, Barman SM, Brooks HL, and Yuan JX. (2019). Ganong's Review of Medical Physiology. 26th ed. ebook by McGraw-Hill Education. 2. Hall JE, and Hall ME. (2021). Guyton and Hall Textbook of Medical Physiology. 14th ed. eBook by Elsevier, Inc. 3. Sherwood L, (2016). Human Physiology From Cells to Systems. 9th ed. eBook by Nelson Education, Ltd. ## Thank You for listening! - The image depicts students walking and sitting outside a university building.