General Physiology 2024 PDF

General physiology, 2024 Dr. Raja. A. Elfakhrei General Physiology (from the Greek physis = nature; logos = study) By definition is the study of biological function...

General physiology, 2024 Dr. Raja. A. Elfakhrei General Physiology (from the Greek physis = nature; logos = study) By definition is the study of biological function of how the body works, from molecular mechanisms within cells to the actions of tissues, organs and systems, and how the organism as a whole accomplishes particular tasks essential for life. In the study of physiology, the emphasis is on “mechanisms ”with questions that begin with the word “how” and answers that involve cause-and-effect sequence. The ultimate objective of physiological research is to understand the normal functioning of cells, organs and systems. A related science— patho-physiology is concerned with how physiological processes are altered in disease or injury. The cell (the basic living unit of the body) Each organ is an aggregate of many different cells held together by intercellular supporting structures. Each type of cell performs one or more particular functions, e.g. the red blood cells transport oxygen from the lungs to the tissues. Although many cells of the body often are markedly different from one another, all of them have certain basic characteristics. Extracellular and intracellular fluid About 60 % of the adult human body is fluid, mainly water solution of ions and other substances. 2/3rd of this fluid is inside the cells and is called intracellular fluid, The other 1/3rd is in the spaces outside the cells and is called extracellular fluid. Homeostasis Homeostasis is the process by which an organism maintains nearly constant conditions in the internal environment. Essentially all organs and tissues of the body perform functions that help maintain these constant conditions. For example, the lungs provide oxygen to the extracellular fluid to replenish the oxygen used by the cells, the kidneys maintain constant ion concentrations, and the gastrointestinal system provides nutrients. All the several variables that the body carefully controls to maintain constant conditions, including body core temperature, oxygen plasma level, arterial blood pressure and blood volume, blood glucose, and ion concentrations, called vital parameters. Thus, homeostasis can also be defined as the control of a vital parameter. 1 General physiology, 2024 Dr. Raja. A. Elfakhrei Fig (1) show homeostasis Homeostatic Control Systems of the Body In order to maintain hemostasis, control system must be able to 1. Detect deviation from normal in the internal environment that needs to be held within normal or narrow limits. 2. Integrate this information with other relevant information. 3. Make appropriate adjustments in order to restore a factor or a parameter to its desired value. Control systems are classified into two type. Intrinsic (local) system, which operates locally within the organs to control functions of the individual parts of the organs. (e.g paracrine and autocrine chemical messengers) Extrinsic system, which operates throughout the entire body to control the interrelations between the organs, that is the nervous and endocrine system (e.g hormones, neurotransmitters, neurohormones). 2 General physiology, 2024 Dr. Raja. A. Elfakhrei Examples of Control Mechanisms 1. Regulation of Oxygen and Carbon Dioxide Concentrations in the ECF Because oxygen is one of the major substances required for chemical reactions in the cells, the body has a special control mechanism to maintain an almost exact and constant oxygen concentration in the extracellular fluid. Hemoglobin combines with oxygen as the blood passes through the lungs. Then, as the blood passes through the tissue capillaries, sufficient oxygen is released to reestablish an adequate concentration of oxygen. Carbon dioxide is a major end product of the oxidative reactions in cells. Hemoglobin reacts with co2 at tissues and releases it to the lungs then to the outside. A higher than normal carbon dioxide concentration in the blood excites the respiratory center, causing a person to breathe rapidly and deeply. This response increases the expiration of carbon dioxide and, therefore, removes the excess carbon dioxide from the blood and tissue fluids. This process continues until the concentration returns to normal. Fig (2) O2 and CO2 regulation in ECF 3 General physiology, 2024 Dr. Raja. A. Elfakhrei 2. Regulation of Arterial Blood Pressure Several systems contribute to the regulation of arterial blood pressure. One of these, the baroreceptor system, is a simple and rapid acting control mechanism. baroreceptors present in the walls of the bifurcation region of the carotid arteries in the neck, and also in the arch of the aorta in the thorax, they are stimulated by stretch of the arterial wall. When the arterial pressure rises too high, the baroreceptors send nerve impulses to the medulla of the brain. These impulses inhibit the vasomotor center, which in turn decreases the number of impulses transmitted from the vasomotor center through the sympathetic nervous system to the heart and blood vessels, causing dilation of the peripheral blood vessels, allowing decreased blood flow through the vessels. Both of these effects decrease the arterial pressure back toward normal. Conversely, a decrease in arterial pressure below normal relaxes the stretch receptors, allowing the vasomotor center to become more active than usual, thereby causing vasoconstriction and increased heart pumping, and raising arterial pressure back toward normal. Fig (3) Baro-receptor reflex 90() 4 General physiology, 2024 Dr. Raja. A. Elfakhrei Fig (4) show Baro-receptor reflex Characteristics of Control Systems Negative Feedback Control Systems Most control systems of the body act by negative feedback, Which is a series of changes that return the factor toward a certain mean value, thus maintaining homeostasis. Examples of negative feedback mechanism In the regulation of carbon dioxide concentration, a high concentration of carbon dioxide in the extracellular fluid causes an increase in pulmonary ventilation. This increase, in turn, decreases the extracellular fluid carbon dioxide concentration because the lungs expire greater amounts of carbon dioxide from the body (i.e. the high concentration of carbon dioxide initiates events that decrease the concentration toward normal, which is negative to the initiating stimulus. Conversely, if the carbon dioxide concentration falls too low, this causes feedback to increase the concentration. This response also is negative to the initiating stimulus. In the arterial pressure regulating mechanisms, a high pressure causes a series of reactions that promote a lowered pressure, or a low pressure causes a series of reactions that promote an elevated pressure. In both instances, these effects are negative with respect to the initiating stimulus. 5 General physiology, 2024 Dr. Raja. A. Elfakhrei Fig (5) Negative feedback control mechanism 6 General physiology, 2024 Dr. Raja. A. Elfakhrei Positive Feedback Control mechanism In some instances, the body uses positive feedback to its advantage. Examples of Positive Feedback Control Blood clotting mechanism: When a blood vessel is ruptured and a clot begins to form, multiple enzymes called clotting factors are activated within the clot itself. Some of these enzymes act on other inactivated enzymes of the adjacent blood, thus causing more blood clotting. This process continues until the hole in the vessel is plugged and bleeding stoppage occurs. Childbirth: When uterine contractions become strong enough for the baby’s head to begin pushing through the cervix, stretch of the cervix ends signals through the uterine muscle back to the body of the uterus, causing even more powerful contractions. Thus, the uterine contractions stretch the cervix, and the cervical stretch causes stronger contractions. When this process becomes powerful enough, the baby is born 7 General physiology, 2024 Dr. Raja. A. Elfakhrei Cell Physiology The cell & its functions The cell is the basic unit of structure and function in the body. Many of the functions of cells are performed by particular sub cellular structures called organelles. The human body contains about 100 trillion cells, each of which is a living structure. Despite the difference between cells, they have some functions in common, like their ability to live, grow and reproduce. Some also show characteristics of metabolism, irritability and even movement or locomotion. Each is specially adapted to perform one particular function To understand the function of organs and other structures of the body, it is essential to understand the basic organization of the cell and the functions of its component parts. Fig (6) the cell 8 General physiology, 2024 Dr. Raja. A. Elfakhrei Organization of the Cell A typical cell has two major parts, which are the nucleus and the cytoplasm. The different substances that make up the cell are collectively called protoplasm. Protoplasm is composed mainly of five basic substances: water, electrolytes, proteins, lipids and carbohydrates. 1. Water:  Presents in most cells, except for fat cells.  It represents 70 to 85 %.  Many cellular chemicals are dissolved in the water. Others are suspended in the water as solid particulates. 2. Ions: The most important ions in the cell are potassium, magnesium, phosphate, sulfate, bicarbonate, and smaller quantities of sodium, chloride, and calcium. 3. Proteins:  After water, the most abundant substances in most cells are proteins.  Normally constitute 10 to 20 % of the cell mass.  Divided into two types: structural proteins and functional proteins. 4. Lipids:  The most important lipids are phospholipids and cholesterol.  Constitute about 2 % of the total cell mass. 5. Carbohydrates: Glycoprotein molecules present in cell membrane and glycogen stored in the cytoplasm. 9 General physiology, 2024 Dr. Raja. A. Elfakhrei Cell membrane (plasma membrane) It envelops the cell, is a thin, elastic structure only 7.5 to 10 nanometers thick. It is composed almost entirely of proteins and lipids. Fig (7) The structure of cell membrane Lipid Barrier of the Cell Membrane The basic lipid bilayer is composed of phospholipid molecules. A phospholipid is an amphipathic molecule, meaning it has both a hydrophobic and a hydrophilic component. A phospholipid molecule has a phosphate group on one end, (the head) and two side-by-side chains of fatty acids that is the lipid (tails). The phosphate group is negatively charged, making the head polar and hydrophilic (water soluble), and are projected to the outer and the inner surfaces of the membrane. Whereas the fatty acid or lipid tails, are uncharged, nonpolar, and hydrophobic (water insoluble), and are present in between (center of membrane). Fig (8) phospholipid bilayer 11 General physiology, 2024 Dr. Raja. A. Elfakhrei Membrane proteins Mostly glycoproteins. There are two types of proteins, integral proteins that protrude all the way through the membrane, and peripheral proteins that are attached only to one surface of the membrane and do not penetrate all the way through. Functions of proteins in the cell membrane  Structural protein: keeps the integrity of the membrane and gives it strength.  Passive channels for passage of ions and water.  Active pumps for active transport of ions across the membrane.  Receptors  Enzymes Fig (9) membrane protein functions The Nucleus The nucleus is the control center of the cell. It is surrounded by nuclear envelope. The nucleus contains large quantities of DNA, which are the genes. The genes determine the characteristics of the cell’s proteins, control and promote reproduction of the cell itself. All cells of the body have a nucleus although some cells, such as red blood cells, lose their nuclei as they mature. Other cells, such as osteoclasts (a type of bone cell) and skeletal muscle cells, contain more than one nucleus. Fig (10) The nucleus 11 General physiology, 2024 Dr. Raja. A. Elfakhrei Nucleoli  From one to four per nucleus.  They are rounded, dense, well-defined nuclear bodies with no surrounding membrane.  The nucleolus produces ribosomal ribonucleic acid(rRNA), which combines with proteins produced in the cytoplasm to form large and small ribosomal subunits. The proteins from the cytoplasm enter the nucleus through nuclear pores, and the ribosomal subunits move from the nucleus through the nuclear pores into the cytoplasm, where one large and one small subunit join to form a ribosome. Ribosomes Ribosomes are the organelles responsible for protein synthesis. There are two types of ribosomes. Free ribosomes, which are not attached to any other organelles in the cytoplasm, and their function is primarily to synthesize proteins used inside the cell. Other ribosomes, which are attached to the endoplasmic reticulum, and their function is to produce proteins that are secreted from the cell. The mitochondria They are sausage-shaped structures in the cytoplasm of cells, that are considered to be the power-houses of the cell, where ATP is made by a process called oxidative phosphorylation. The inner cavity of the mitochondria is filled with enzymes that are necessary for extracting energy from nutrients. The liberated energy is used to synthesize adenosine triphosphate (ATP). ATP is then transported out of the mitochondria and diffuses to the cell to be used or released as energy for performing three major categories of cellular functions: 1. Transport of substances through multiple membranes in the cell. 2. Synthesis of chemical compounds throughout the cell. 3. Mechanical work (supply the energy needed during muscle contraction). Fig (11) The mitochondria 12 General physiology, 2024 Dr. Raja. A. Elfakhrei The Endoplasmic reticulum It is a cytoplasmic network of flatted and tubular membrane bound sacs that store proteins and lipids. There are two types: 1. Rough endoplasmic reticulum (RER). It bears ribosomes. It is abundant in cells that are active in protein synthesis and secretion (e.g exocrine and endocrine glands) 2. Smooth endoplasmic reticulum (SER) It does not bear ribosomes. Its functions are : glycogen breakdown, synthesis of cholesterol and phospholipids. detoxification of drugs and poisons and storage of Ca 2+ in striated muscle cells. Fig (12) The Endoplasmic reticulum Golgi Complex The Golgi complex consists of a stack of several flattened sacs located near the nucleus. Within these sacs cavities called cisternae. Golgi complex is responsible for packaging proteins to be exported as vesicles that leave the Golgi complex. These vesicles may then become lysosomes, or secretory vesicles. Fig (13) Golgi Complex 13 General physiology, 2024 Dr. Raja. A. Elfakhrei lysosomes They are membranous sacs filled with digestive enzymes. The enzymes are made up by the ribosomes on the endoplasmic reticulum, and then released into the lysosomes via Golgi complex. Lysosomes’ functions are: 1- to digest bacteria engulfed by white blood cells. 2- to digest food particles ingested by the cells. 3- to remove aged or damaged cellular organelles. Fig (14) lysosomes 14 General physiology, 2024 Dr. Raja. A. Elfakhrei The body fluid In the average 70-kilogram adult human, the total body water is about 60 % of the body weight. However this percentage can change depending on age, gender, and percentage of body fat. It is distributed mainly between two compartments: The extracellular fluid and the intracellular fluid The extracellular fluid is divided into the interstitial fluid and the blood plasma another small compartment called transcellular fluid. This compartment includes fluid in the synovial, peritoneal, pericardial, and intraocular spaces, and the cerebrospinal fluid; it is considered to be a specialized type of extracellular fluid, although in some cases, its composition may differ from that of the plasma or interstitial fluid. All the transcellular fluids together constitute about 1 to 2 liters Fig (15) body fluid 15 General physiology, 2024 Dr. Raja. A. Elfakhrei Table (1) percentage of body fluid in a 70 Kg man Compartment % of body water Volume in a 70kg man Total body water (TBW) 60 % 42 L Intra- cellular fluid (ICF) 40% 28 L Extra- cellular fluid (ECF) 20% 14 L i. Interstitial fluid (ISF) 15% 10.5 L ii. Plasma 5% 3.5 L plasma and interstitial fluids have about the same composition except for proteins, which have a higher concentration in the plasma. 16 General physiology, 2024 Dr. Raja. A. Elfakhrei Measurement of TBW (The Indicator-Dilution Principle) 1. A known amount of an indicator substance is injected (IV) 2. Sufficient time is allowed for complete distribution of the indicator , then its concentration in the plasma is determined 3. The volume of distribution (TBW) is calculated by dividing the injected amount of the indicator by its concentration in the plasma Amount of substance injected = amount of substance in the body fluid C×V =C1×V1 V1= C×V C1 Indicators for measurement of body compartments Total body water: Uses a substance that diffuses freely into all fluid compartments:  Radioactive water  Deuterium oxide  Tritiated water Extracellular fluid volume Non-metabolised substances  Mannitol  Inulin  Sucrose Plasma volume  Evan blue dye Intracellular fluid volume Can be measured indirectly by : ICF= TBW- ECF Interstitial fluid ECF- plasma 17 General physiology, 2024 Dr. Raja. A. Elfakhrei Fig (16) indicators used to measure different body fluid compartment 18 General physiology, 2024 Dr. Raja. A. Elfakhrei Osmosis It is the net diffusion of water (the solvent) across the selectively permeable membrane from a region of high water concentration to one that has a lower water concentration. There are two requirements for osmosis: (1) a difference in the concentration of a solute on the two sides of a selectively permeable membrane (2) the membrane must be relatively impermeable to the solute. Solutes that cannot freely pass through the membrane can promote the osmotic movement of water and are said to be osmotically active. The total number of particles in a solution is measured in osmoles. One osmole (osm) is equal to 1 mole (mol) (6.02 ×1023) of solute particles. Fig (17) osmosis 19 General physiology, 2024 Dr. Raja. A. Elfakhrei osmotic pressure is the pressure needed to just stop osmosis The greater the solute concentration of a solution, the greater its osmotic pressure. Examples Pure water has an osmotic pressure of zero 360 g/L glucose solution has twice the osmotic pressure of a 180 g/L glucose solution one molecule of albumin (M.wt70,000) has the same osmotic effect as one molecule of glucose with (M. wt 180) One molecule of sodium chloride has two osmotically active particles,Na+ and Cl–, and therefore has twice the osmotic effect of either an albumin molecule or a glucose molecule Osmolality number of osmoles per kilogram of water Osmolarity number of osmole per liter of water milliosmole (mOsm) equals 1/1000 osmole (commonly used). osmotic pressure (p) can be calculated according to van’t Hoff’s law as p =n CRT where : C is the concentration of solutes in osmoles per Liter R is the ideal gas constant T is the absolute temperature Note that, Plasma omolarity is about 300 mOsm/l. Fluid that have an osmolality of 300 is said to be iso-osmotic < 300 hypoosmotic , >300 hyperosmotic 21 General physiology, 2024 Dr. Raja. A. Elfakhrei Tonicity  Is determined by osmolarity of the solution as well as by the permeability properties of the cell membrane  Tonicity determines cell volume 1. Non-permeant solutes Sucrose cannot cross the plasma membrane of cells. Therefore, if a cell is placed in a sucrose solution whose osmolality (300 mOsm/kg H2O), cell volume will not change because the solution is isotonic A 100–mOsm/kg H2O sucrose solution is hypotonic. Water molecules will move across the membrane from ECF to ICF following the osmotic gradient, and the cell will swell a 500–mOsm/kg H2O sucrose solution is hypertonic: Water will be drawn out of the cell by osmosis, causing the cell to shrink 2. Permeant solutes Urea is a small (60 MW) molecule that permeates the membranes of most cells via a urea transporter (UT). Thus, although 300–mOsm/kg H2O urea is iso- osmotic to plasma, it is not isotonic. When a cell is placed in a 300–mOsm/kg H2O urea solution, urea crosses the membrane via UT and raises ICF osmolality. Water then follows urea by osmosis, and the cell swells. A 300–mOsm/kg H2O urea solution is, thus, considered to be hypotonic 3. Mixed solutions A solution containing 300 mOsm/kg H2O urea plus 300 mOsm/kg H2O sucrose has an osmolarity of 600 mOsm/ kg H2O and is, thus, hyperosmotic relative to the ICF. It is also functionally isotonic, however, because urea rapidly crosses the membrane until the intracellular and extracellular urea concentrations equilibrate at 150 mOsm/kg H2O. With solution osmolality on both sides of the membrane now standing at 450 mOsm/kg H2O, the driving force for osmosis is zero, and cell volume remains un- changed Types of solutions Isotonic solution Has the same osmolarity of plasma (300mlosm /l H2O ) It will not produce any change in cell volume solutions injected into the blood or into tissues must be isotonic 21 General physiology, 2024 Dr. Raja. A. Elfakhrei e.g 0.9 % sodium chloride 5% glucose solution. hypertonic solution the solution usually has a higher concentration of solutes than plasma (>300mlosm /l H2O) Water moves by osmosis from the cell into the hypertonic solution, resulting in cell shrinkage e.g Solutions of Nacl with a concentration > 0.9 % hypotonic solution the solution usually has a lower concentration of solutes and a higher concentration of water than plasma. Water moves by osmosis into the cell, causing it to swell. If the cell swells enough, it can rupture, e.g Solutions of Nacl with a concentration < 0.9 % Fig (18) osmotic behavior of RBCs membrane 22 General physiology, 2024 Dr. Raja. A. Elfakhrei Transport across cell membrane Cell transport: A biological process through which molecules & ions pass into and out of cells, crossing the semipermeable membrane. It is important as it allows nutrients to enter and waste products to exit, and also helps in the regulation of intracellular environment (homeostasis) & temperature. The membrane permeability is accomplished by the lipid bilayer that makes it difficult for all molecules and ions to pass freely into the cell, except for the hydrophobic (lipid soluble) ones. Other hydrophilic molecules & ions can enter the cell through protein channels or carriers and vesicles. Classifications of cell transport: There are two classifications can be described I) Based on presence or absence of a carrier: 1. Carrier-mediated transport a. Facilitated diffusion b. Active transport 2. Non-carrier-mediated transport a. Simple diffusion (diffusion that is not carrier-mediated) of lipid-soluble molecules through the phospholipid layers of the plasma membrane b. Osmosis: Simple diffusion of water molecules through aquaporin (water) channels in the plasma membrane c. Facilitated diffusion of ions through membrane channel proteins in the plasma membrane. II) Based on energy requirement 1. Passive transport Passive transport by definition is the net movement of molecules and ions across a membrane from higher to lower concentration (down a concentration gradient) for the specific ions & molecules. It does not require metabolic energy (ATP) Passive transport includes: 23 General physiology, 2024 Dr. Raja. A. Elfakhrei 1- All of the non-carrier-mediated diffusion processes (simple diffusion of lipid- soluble molecules, osmosis and facilitated diffusion of ions) 2- The carrier-mediated facilitated diffusion 2. Active transport Active transport by definition is the net movement of molecules and ions across a membrane from the region of lower to the region of higher concentrations. Thus, using metabolic energy (ATP) is required. Active transport includes: 1- Carrier-mediated active transport 2- The transport of large molecules via vesicles: a. Endocytosis b. Exocytosis Passive Diffusion/transport 1. Simple diffusion through the lipid bilayer  A process in which ions & molecules move directly through the intermolecular spaces or pores, from an area of higher concentration to an area of lower concentration (down concentration gradient) for the specific molecule or ion.  This process does not need intermediary protein carriers.  The passing molecules are usually hydrophobic (i.e. lipid soluble) in nature, such as gases O2& CO2, Lipids as steroid hormones & lipid-soluble molecules as alcohols & some vitamins. 2. Diffusion through aquaporin channels (Osmosis)  The Movement of water across a selectively permeable membrane from anareaoflower solute concentration into an area of higher solute concentration.  Usually occurs either by simple diffusion through the lipid bilayer or through a specific protein channel called aquaporin. 3. Facilitated Diffusion: Facilitate: to aid or help  Facilitated diffusion by definition is the diffusion of molecules from an area of higher concentration to an area of lower concentration for that specific molecule with the help of channel or carrier proteins, and no energy required. 24 General physiology, 2024 Dr. Raja. A. Elfakhrei  The facilitated diffusion rate usually is limited by the number of proteins channels or carriers present in the membrane.  Types of facilitated diffusion: a) Channel mediated facilitated diffusion. b) Carrier-mediated facilitated diffusion. a) Channel mediated facilitated diffusion Most non-lipid-soluble molecules and ions pass through the transport proteins or protein channels. These protein channels are characterized by 1. They are often selectively permeable to certain substances (e.g. Na+ channel and K+ channel) 2. Many of the channels are gated channels. Types of gates: 1. Voltage gating The molecular conformation of the gate responds to the electrical potential across the cell membrane. 2. Chemical (ligand) gating Some protein channel gates are opened by the binding of a chemical substance (a ligand) with the protein; this causes a conformational or a chemical change in the protein molecule that opens or closes the gate. (e.g. acetylcholine channel). **Some channels are leaky i.e. open all the time b) Carrier-mediated facilitated diffusion Glucose and most of the amino acids are transported by this way. Carrier mediated transport has three characteristics: specificity, competition, and saturation. 1) Specificity means that each transport protein moves particular molecules or ions, but not others. 2) Competition Although transport proteins exhibit specificity, a transport protein may transport very similar substances. 3) Saturation means that the rate of movement of molecules or ions across the membrane is limited by the number of available transport proteins. As the concentration of a transported substance increases, more transport proteins 25 General physiology, 2024 Dr. Raja. A. Elfakhrei become involved with transporting the substance, and the rate at which the substance is moved across the plasma membrane increases. Once the concentration of the substance is increased so that all the transport proteins are in use, the rate of movement remains constant, even though the concentration of the substance increases further. The difference between simple diffusion and facilitated diffusion is that, as the concentration of the diffusing substance increases, the rate of simple diffusion continues to increase proportionately, but in the case of facilitated diffusion, the rate of diffusion cannot rise greater than the Vmax level (Fig.17). Fig (19)The difference between simple diffusion and facilitated diffusion Movement of ions or molecules by carrier proteins can be classified as uniport, symport, or antiport. i. Uniport is the movement of one specific ion or molecule across the membrane ii. Symport is the movement of two or more different ions or molecules in the same direction across the plasma membrane (Na+ and glucose) iii. Antiport is the movement of two or more different ions or molecules in opposite directions across the plasma membrane (the movement of Na+into a cell coupled with the movement of H+out of the cell) 26 General physiology, 2024 Dr. Raja. A. Elfakhrei Factors that affect net rate of Diffusion  The concentration gradient of the solute across the membrane.  The permeability of the membrane to the solute.  The trans-membrane voltage gradient.  The molecular weight of the solute.  The membrane surface area.  The distance over which diffusion occurs. Fig (20) simple and passive diffusion 27 General physiology, 2024 Dr. Raja. A. Elfakhrei Fig (21) facilitated diffusion 28 General physiology, 2024 Dr. Raja. A. Elfakhrei Active transport  Movement of molecules or ions “uphill” against a concentration gradient (or “uphill” against an electrical or pressure gradient).  Energy is required.  Requires protein carriers called Pumps.  Active transport is divided into two types according to the source of the energy used to cause the transport: i. primary active transport ii. secondary active transport  The transport of large molecule by vesicles (vesicular transport) is also considered an active transport as it requires energy but not pump. 1- Primary active transport This transport uses energy derived directly from the breakdown of adenosine triphosphate (ATP) examples: Sodium-potassium pump or Na+ /K+-ATPase  It is found in the plasma membrane.  It has three receptor sites for binding sodium ions on the inside of the cell, and two receptor sites for potassium ions on the outside.  The inside portion of this protein near the sodium binding sites has ATPase activity.  It is responsible for maintaining the low sodium and high potassium concentrations in the cytoplasm. This creates positivity outside the cell but leaves a deficit of positive ions inside the cell; that is, it causes negativity on the inside. Thus creates an electrical potential across the cell membrane. Fig (22) Na+- K+ pump 29 General physiology, 2024 Dr. Raja. A. Elfakhrei Calcium pump  It is found in the plasma membrane, in the membrane of the endoplasmic reticulum in muscle cells.  They pump calcium ions from the cytosol of the cell either into the extracellular space or into the lumen of these organelles. The organelles store calcium and, as a result, help maintain a low cytosolic concentration of this ion. Fig (23) calcium pump 31 General physiology, 2024 Dr. Raja. A. Elfakhrei The H+/K+-ATPase It is present in the luminal membrane of the parietal cells in oxyntic (acid-secreting) glands of the stomach. By pumping protons into the lumen of the stomach in exchange for potassium ions, this pump maintains the low pH in the stomach that is necessary for proper digestion. 2- Secondary active transport The concentration gradient established by the active transport of one substance provides energy to move a second substance. Example: Co-Transport of Glucose and Amino Acids Along with Sodium Ions It occurs especially through the epithelial cells of the intestinal tract and the renal tubules of the kidneys. Na+ are actively pumped out of a cell, establishing a higher concentration of Na+ outside the cell than inside. The movement of Na +down its concentration gradient back into the cell provides the energy necessary to move glucose into the cell against its concentration gradient. In this example, a symporter moves Na+ and glucose into the cell together. Sodium co-transport of the amino acids occurs in the same manner as for glucose. FIG (24 ) Na – Glucose Co Transport 31 General physiology, 2024 Dr. Raja. A. Elfakhrei Sodium Counter-Transport of Calcium and Hydrogen Ions  Sodium-calcium counter-transport occurs through all cell membranes, with sodium ions moving to the interior and calcium ions to the exterior, both bound to the same transport protein in a counter transport mode.  Sodium-hydrogen counter-transport occurs in several tissues (e.g. in the proximal tubules of the kidneys) where sodium ions move from the lumen of the tubule to the interior of the tubular cell, while hydrogen ions are counter transported into the tubule lumen. Transport of large molecules Vesicular Transport (a type of active transport) 1- Endocytosis A process by which cells take up large molecules such as polysaccharides and proteins, and it requires energy so it is active process. Forms of Endocytosis a) Pinocytosis: The plasma membrane invaginates to produce a deep, narrow furrow. The membrane near the surface of this furrow then fuses, and a small vesicle containing the extracellular fluid is pinched off and enters the cell. 32 General physiology, 2024 Dr. Raja. A. Elfakhrei Fig (25) Pincocytosis b) Receptor-mediated Pinocytosis: In receptor-mediated endocytosis, the interaction of specific molecules in the extracellular fluid with specific membrane receptor proteins causes the membrane to invaginate, fuse, and pinch off to form a vesicle. Vesicles formed in this way contain extracellular fluid and molecules that could not have passed by other means into the cell (e.g. Cholesterol) Fig (26) receptor mediated Pincocytosis 33 General physiology, 2024 Dr. Raja. A. Elfakhrei c) Phagocytosis: This process occurs in the same way as pinocytosis, except that it involves large Particles (e.g. bacteria, viruses) rather than molecules. Tissue macrophages and some of the white blood cells have a phagocytic activity Fig (27) phagocytosis 34 General physiology, 2024 Dr. Raja. A. Elfakhrei 2- Exocytosis Exocytosis, by definition, is the movement of materials out of cells by vesicles. Secretary vesicles accumulate materials for release from cells. The secretory vesicles move to the plasma membrane, where the vesicle membrane fuses with the plasma membrane, and the material in the vesicle is eliminated from the cell. Examples of exocytosis are the secretion of digestive enzymes by the pancreas, of mucus by the salivary glands, and of milk from the mammary glands. Fig (28) Exocytosis 35 General physiology, 2024 Dr. Raja. A. Elfakhrei Cell Communication The body’s various organs must work closely together to ensure the well-being of the individual as a whole. Cooperation requires communication between organs and cells within organs. INTERCELLULAR COMMUNICATION Some cells contact and communicate with each other directly via: a) Gap junctions These are regulated pores that allow for exchanging chemical and electrical information and play a vital role in coordination of cardiac excitation and contraction. b) Hormones: which are chemicals produced by endocrine glands and some non endocrine tissues that are carried to distant targets via blood. Insulin, for example, is released into the circulation by pancreatic islet cells to be carried to muscle, adipose tissue, and the liver. Paracrines :are released from cells in very close proximity to their target. For example, the endothelial cells that line blood vessels release nitric oxide as a way of communicating with the smooth muscle cells that make up the vessel walls. Autocrines: are messengers bind to receptors on the same cell that released them, creating a negative feedback pathway that modulates autocrine release. 36 General physiology, 2024 Dr. Raja. A. Elfakhrei Fig ( 29 ) intercellular communications 37 General physiology, 2024 Dr. Raja. A. Elfakhrei INTRACELLULAR SIGNALING Once a chemical message arrives, it is recognized by the target cell and then transduced into a form that can modify cell function. Recognition is accomplished by using receptors, which serve as Hormone or neurotransmitter binding site that elicits a changes that end with a cellular response. Receptors are typically integral membrane proteins such as A. ligand-gated channels, B. G protein–coupled receptors (GPCRs) C. enzyme- associated receptors. D. intracellular receptors. Fig (30) intracellular communications 38 General physiology, 2024 Dr. Raja. A. Elfakhrei A. Channels Ligand-gated ion channels facilitate communication between neurons and their target cells, including other neurons. For example, the nicotinic acetylcholine (ACh) receptor is a ligand-gated ion channel that allows skeletal muscle cells to respond to excitatory impulse from motor neurons. Ach binding to its receptor causes a conformational change that opens the channel and allows ions such as Na+_, K+_, Ca2, and Cl_ to flow across the membrane through pores. Charge movement across the membrane constitutes an electrical signal that influences target cell activity directly. B. G protein–coupled receptors GPCRs sense and transduce a majority of chemical signals. They are found in both neural and non-neural tissues. which then activates one or more second messenger pathways. Second messengers include : cyclic 3_5 adenosine monophosphate (cAMP), cyclic3_5_-guanosine monophosphate (cGMP), and inositol trisphosphate (IP3) Fig (31) G- protein couples receptor 39 General physiology, 2024 Dr. Raja. A. Elfakhrei I) cAMP signaling pathway: 1. The hormone binds to its receptor on the outer surface of the target cell’s plasma membrane. 2. Hormone-receptor interaction acts by means of G-proteins to stimulate the activity of adenylate cyclase on the cytoplasmic side of the membrane. 3. Activated adenylate cyclase catalyzes the conversion of ATP to cyclic AMP (cAMP) within the cytoplasm. 4. Cyclic AMP activates protein kinase enzymes that were already present in the cytoplasm in an inactive state. 5. Activated cAMP-dependent protein kinase transfers phosphate groups to (phosphorylates) other enzymes in the cytoplasm. 6. The activity of specific enzymes is either increased or inhibited by phosphorylation. 7. Altered enzyme activity mediates the target cell’s response to the hormone Fig (32) cAMP pathway 41 General physiology, 2024 Dr. Raja. A. Elfakhrei Hormones that works through activation of cAMP: Adrenocorticotropic hormone (ACTH), Angiotensin II, Calcitonin Catecholamines (β receptors) Corticotropin-releasing hormone (CRH) Follicle-stimulating hormone (FSH) 1. IP3 signaling pathway: a G-protein subunit liberates three different second messengers via activation of phospholipase C (PLC). The messengers are IP3, diacylglycerol (DAG), and Ca2 1. The hormone binds to its receptor on the outer surface of the target cell’s plasma membrane. 2. Hormone-receptor interaction stimulates the activity of a membrane enzyme, phospholipase C. 3. Activated phospholipase C catalyzes the conversion of particular phospholipids in the membrane to inositol triphosphate (IP3) and another derivative, diacylglycerol. 4. Inositol triphosphate enters the cytoplasm and diffuses to the endoplasmic reticulum, where it binds to its receptor proteins and causes the opening of Ca2+ channels. 5. Since the endoplasmic reticulum accumulates Ca2+ by active transport, there exists a steep Ca2+ concentration gradient favoring the diffusion of Ca2+ into the cytoplasm. 6. Ca2+ that enters the cytoplasm binds to and activates a protein called calmodulin. 7. Activated calmodulin, in turn, activates protein kinase, which phosphorylates other enzyme proteins. 8. Altered enzyme activity mediates the target cell’s response to the hormone Hormones that work through this pathway: Angiotensin II (vascular smooth muscle) Catecholamines (α receptors) Gonadotropin-releasing hormone (GnRH) Growth hormone–releasing hormone (GHRH) 41 General physiology, 2024 Dr. Raja. A. Elfakhrei Fig (33) IP3 signaling pathway C. Catalytic receptors Some ligands bind to membrane receptors that either associate with an enzyme or that have intrinsic catalytic activity. For example, natriuretic peptides influence renal function via a receptor guanylyl cyclase and cGMP formation. Most catalytic receptors are tyrosine kinases (TRKs), the most common example being the insulin receptor. D. Intracellular receptors A fourth receptor class is located intracellularly includes receptors for thyroid hormone and a majority of steroid hormones. It influences cell function by binding to DNA and altering gene expression. Some of the receptors are cytoplasmic, whereas others are nuclear the receptor induces gene transcription, and the product alters cell function 42 General physiology, 2024 Dr. Raja. A. Elfakhrei Fig (34) intracellular receptor 43 General physiology, 2024 Dr. Raja. A. Elfakhrei 44