HAP- cellular level of organization.pptx

detail study of cell

1. CELLULAR LEVEL OF ORGANIZATION 1 Mrs. Gayatri Thapa Human Anatomy & Physiology-I

2. WHAT ARE CELLS? Cells are the smallest functional units of the body. They are grouped together to form tissues  organs  system . Systems thereby maintains homeostasis contributing to the health of the individual. 2

3. STRUCTURE AND FUNCTIONS OF CELL 3 The human body develops from a single cell called zygote (fusion of ovum & spermatozoon). Then the cells with different structures and functions develop but they have same genetic makeup as the zygote. Cell consists of a plasma membrane/cell membrane inside which floats various organelles in a watery fluid called Cytosol.

4. Different organelles Organelles are small structures with highly specialized functions. Cell organelles are- Nucleus Mitochondria Endoplasmic reticulum Golgi apparatus Ribosome Lysosomes Microfilaments and microtubules Centrosome Proteosome 4

5. PLASMA MEMBRANE 5 FIG: PLASMA MEMBRANE

6. PLASMA MEMBRANE A selective permeable , lipoprotein membrane that separates the cell content from the external environment is known as plasma membrane. It consists of two layers of phospholipids (fatty substances) and some protein molecules embedded in them. The bigger proteins extending through the membrane acts as a channel for the passage of electrolytes and other non-lipid-soluble substances. Phospholipids bilayer is arranged like a sandwich with hydrophilic head (aligned on the outer surfaces of the membrane) which is electrically charged and a hydrophobic tail which has no charge. 6 FIG: PLASMA MEMBRANE

7. FUNCTIONS OF PLASMA MEMBRANE TRANSPORT- the proteins and enzymes present in the membrane are involved in the transport of certain substances such as sugar, sodium and other ions across the membrane. PROTECTION- protects the internal structures of the cell and different organelles as well as maintains the shape of the cell. ACTS AS SELECTIVE PERMEABLE MEMBRANE- helps the transport of selective materials from and into the cells. CHEMORECEPTION- The cell membrane of certain animals contains chemoreceptors which receive chemical stimulation. TRANSMISSION- The transmission of the nerve impulse takes place at the surface membrane of the nerve cells. ACTS AS SPECIFIC RECEPTORS- For certain hormones and chemical messengers, membrane protein acts as specific receptors. 7

8. NUCLEUS Every cell in the body has a nucleus except mature erythrocytes (RBC) whereas Skeletal muscle and some other cells contain several nuclei. It is the membrane bound cellular structure containing genetic material DNA in chromosome and generally located at the centre of the cell. It is the largest organelle and possess its own membrane called nuclear membrane . It consists of – the nuclear membrane, nucleoplasm, the nucleolus and chromatin fibres . Nuclear membrane- allows the free exchange of ions between nucleoplasm and cytoplasm , protects the internal structure of nucleus & helps in the formation of Golgi bodies and ER. Nucleolus- RNA production, ribosome formation. 8

9. NUCLEUS The nucleus contains the genetic material which is built from DNA and proteins called histones coiled together forming a fine network of threads called chromatin. During cell division this chromatin replicates and becomes more tightly coiled forming chromosomes . The functional subunits of chromosomes are called genes. General functions of nucleus- Acts as life centre and controls nutritive, respiratory and other vital activities of the cell. Helps in the growth and cell division. The DNA present in the nucleus determines the genetic makeup of the cell. 9

10. MITOCHONDRIA They are sausage shaped structures in the cytoplasm. They are also called the ‘power house’ of the cell as they provide energy to the cell. Chemical energy (in the form of ATP ) is made available in the cell by aerobic respiration( process where oxygen is required ). It is needed for the synthesis of ATP, which releases energy when the cell breaks it down. 10

11. MITOCHONDRIA A mitochondrion consists of two unit membranes, two chambers, mitochondrial matrix and mitochondrial particles. TWO UNIT MEMBANES : One outer membrane and one inner membrane. Each membrane is tri-laminar ( lipo -protein). CHAMBERS: Outer chamber is the space between the outer and inner membrane which is filled with watery fluid and the inner chamber is covered by the inner membrane which contains mitochondrial matrix. MITOCHONDRIAL MATRIX: They contains dense granules, ribosomes and mitochondrial DNA. The enzymes of the krebs cycle are located in the matrix. 11

12. FUNCTION OF MITOCHONDRIA ACTS AS A POWER HOUSE : It is the site for the formation of ATP which is a high energy rich substance that supply 95% of energy to the cell. Different enzymes present in the mitochondria help in oxidative phosphorylation. CELL RESPIRATION : mitochondria are the respiratory organelles of the cell. Cell respiration includes: glycolysis, oxidation of pyruvic acid, kreb’s cycle and oxidative phosphorylation. OXIDATION OF FAT : fatty acids of fats are oxidized at mitochondria. SYNTHESIS OF LIPID : it controls the synthesis of phospholipids. 12

13. RIBOSOME Ribosomes are tiny granules composed of RNA and protein. Synthesis of protein from amino acids takes place using RNA. Ribosomes are also found on the outer surface of rough ER. There are two types of ribosomes- 70S and 80S ribosome. 70S (30S+50S) ribosome are smaller ribosome and are found in prokaryotic cell whereas 80S (40S+60S) ribosome are found in eukaryotic cell. ‘S’ refers to Svedberg unit which is the co-efficient that shows how fast a cell organelle sediments in a ultra centrifuge. FUNCTIONS: acts as a protein factories as it synthesizes protein. It also helps in fat metabolism. 13

14. ENDOPLASMIC RETICULUM It is a series of interconnection membranous canals in the cytoplasm. Two types: smooth ER and rough ER. Smooth ER synthesizes lipids and steroid hormones; It also detoxify some drugs. Rough ER possess ribosomes and synthesizes protein . ER has three parts- cisternae, vesicles and tubules . They remain bounded by the single unit membrane. FUNCTIONS MECHANICAL SUPPORT: ER forms the skeletal framework of the cell and gives support to the cytoplasmic matrix. CIRCULATION AND EXCHANGE: it acts as the intracellular transport system for various substances and also helps to exchange the materials between nucleus and cytoplasm. SYNTHESIS AND STORAGE: Ribosome present in rough ER synthesize protein and smooth ER synthesize lipids, glycogen, cholesterol etc. 14

15. GOLGI APPARATUS Consists of stacks of flattened membranous sacs. The proteins from ER move to the Golgi apparatus  packaged into membrane bound vesicles called secretory granules  when needed move to the plasma membrane through which the proteins are exported. Different parts are: cisternae, small vesicles, large vacuoles . FUNCTIONS FORMATION OF SECRETORY VESICLES: Two terminal ends of Golgi cisternae are pinched off to form secretory vesicles which contains granules. These granules discharge their contents outside through the cell membrane. Therefore, secretion is the main function of Golgi bodies. FORMATION OF PLASMA MEMBRANE: Secretory granules originating from Golgi bodies fuse with plasma membrane and forms new plasma membrane. FORMATION OF LYSOSOME - formed by budding from the golgi complex. ROLE IN PROTEIN SECRETION : proteins formed by ribosomes goes to Golgi bodies where it is concentrated as the zymogen granules. These granules are released from the Golgi bodies and migrates to the surface of the cell. 15

16. LYSOSOME Secretory vesicles formed by the Golgi apparatus. Bounded by a single lipoprotein membrane . Contains vacuolated, granular, dense material rich in acid, phosphates and other enzymes. They contain lysosomal hydrolase enzymes (hydrolytic enzymes) that digests most biological substances. Lysosome thus, separates these enzymes from the rest of the cellular contents, otherwise these enzymes could cause severe damage to the cell. For this reason, lysosomes are called ‘suicidal bags’. They contain enzymes involved in breaking down fragments of organelles and large molecules like RNA, DNA, carbohydrates, protein inside the cell that are then either recycled or extruded from the cell as waste material. Lysosomes in white blood cells contain enzymes that digest foreign material such as microbes. 16 FUNCTIONS: Intracellular digestion- digest substances within the cell as well as exogenous materials. Extracellular digestion- lysosomal enzymes may release outside the cell and cause hydrolysis of extracellular substances. Liberation of energy- During starvation, it liberates energy by digesting the stored carbs, protein and fat. Secretion of hormones- the epithelial cells of thyroid gland enriched in lysosome helps in the secretion of thyroid hormone. Autolysis or autophagy- In certain pathological conditions the lysosomes start to digest the various cell organelles.

17. MICROFILAMENTS AND MICROTUBULES Microtubules- largest, long, unbranched hollow tube- like structures. Made up of tubulin protein. Responsible for providing shape of the cell. Helps in the movement of organelles like- secretory vesicles, chromosomes, cilia and flagella. 17

18. MICROFILAMENTS AND MICROTUBULES Microfilaments – Thin tiny fibres made of actin protein. provide structural support and maintain the characteristic shape of the cell. Helps in muscle contraction, cell division and cell locomotion. Gives mechanical support to microvilli present in the plasma-membrane. 18

19. CENTROSOME Consists of a pair of centrioles oriented at right angles They are microtubule organizing centres located close to the nucleus. They help in formation of mitotic spindle fibres during cell division. 19 PROTEOSOME Barrel shaped structures found in nucleus and cytosol. Contains protease enzyme which catalyzes the breakdown of larger molecules to smaller molecules.

20. TRANSPORT ACROSS CELL MEMBRANE 20

21. TRANSPORT ACROSS CELL MEMBRANE Cell membrane provides a selective barrier to substances entering or leaving the cell (selective permeability). This regulates the composition of its internal environment. Particle size is important as many small molecules like water can pass freely across the membrane by simple diffusion while large molecules cannot and may therefore be confined to either the interstitial fluid or the intracellular fluid. Pores or specific channels in the plasma membrane allows certain substances but not others. The membrane is also studded with specialized pumps or carriers that import/export the particles. Selective permeability ensures that the chemical composition of the fluid inside cells is different from the interstitial fluid that bathes them. 21

22. TRANSPORT MECHANISMS PASSIVE TRANSPORT- energy not required. (diffusion, facilitated diffusion, osmosis). ACTIVE TRANSPORT- energy required. (The sodium-potassium pump). BULK TRANSPORT- Pinocytosis and exocytosis. 22

23. PASSIVE TRANSPORT This occurs when the substances can cross the semipermeable membrane and organelle membranes and move down the concentration gradient (downhill) without using energy. DIFFUSION: Movement of molecules from an area of higher concentration to an area of lower concentration. Only the small molecules and soluble enough to cross the membrane can diffuse through. E.g. diffusion of oxygen through the walls of alveoli where oxygen concentration is high into the blood stream where oxygen concentration is low. Lipid soluble substances such as O 2 , CO 2 , fatty acids and steroids cross the membrane by dissolving in the lipid part of the membrane. Water soluble materials e.g. sodium, potassium and calcium, cross the membrane by passing through water-filled channels (PORINS). 23

24. PASSIVE TRANSPORT FACILITATED DIFFUSION: This process is used by those substances that are unable to diffuse through the semipermeable membrane. E.g. glucose, amino acids. Specialized protein carrier molecules in the membrane have specific sites that attract and bind substances to be transferred, like a lock and key mechanism. The carrier then changes its shape and deposits the substance on the other side of the membrane. These carrier sites are specific and can be used by only one substance. 24

25. PASSIVE TRANSPORT OSMOSIS: The movement of solvent molecules through a semipermeable membrane from a region of higher concentration to the region of lower concentration of a solvent until the equilibrium is reached. 25

26. ACTIVE TRANSPORT In this process the substances can be transported up their concentration gradient (uphill) i.e. from lower concentration to higher concentration with the expenditure of energy (against the concentration gradient). This energy is a chemical energy in the form of adenosine triphosphate (ATP). ATP drives the specialized protein carrier molecules present in the membrane to transport the substances across the membrane in either direction. 26

27. ACTIVE TRANSPORT Primary Active Transport- The carrier protein (pumps) is activated by the energy provided by ATP  transports substances across cell membrane. At a time, only one solute is transported against the concentration gradient, it is called uniporter and also the energy is utilized directly, it is called direct transport . Secondary Active Transport- The energy is not used directly from ATP to transport the substances against concentration gradient. Instead, the ions (Na + and H +) uses the energy stored in another molecule’s gradient . 2 types- 1. Sympoter - Transporters that transports the substances into the same direction (Glucose/Na + symport,). 2. Anti-porter- Transporters that transports the substances into the opposite direction (Na + /H + antiporter). 27

28. ACTIVE TRANSPORT The sodium-potassium pump: All cells possess this pump which indirectly supports other transport mechanisms such as glucose uptake and is essential in maintaining the electrical gradient needed to generate action potentials in nerve and muscle cells. This active transport mechanism maintains the unequal concentrations of sodium (Na + ) and potassium (K + )ions on either side of the plasma membrane. For this process, it requires up to 30% of the cellular ATP. Potassium levels are higher inside the cell than outside. It is the principle intracellular cation whereas sodium levels are higher outside the cell and is a principle extracellular cation. In order to maintain their concentration gradients, excess sodium is constantly pumped out by the sodium-potassium pump. 28

29. BULK TRANSPORT Transfer of too large particles across the plasma membrane occurs by pinocytosis (cell-drinking) or phagocytosis (cell-eating). These particles are engulfed by extensions of the cytoplasm which enclose them forming a membrane-bound vacuole. Pinocytosis allows the cell to bring in fluid. In phagocytosis, larger particles (cell fragments, foreign materials, microbes) are taken into the cell. Lysosomes then adhere to the vacuole membrane, releasing enzymes that digest the content. Extrusion of waste materials by the reverse process through the plasma membrane is called exocytosis. Vesicles formed by the Golgi apparatus usually leave the cell in this way, so do any digestible residues of phagocytosis. 29

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31. CELL DIVISION 31

32. CELL DIVISION 32 The process by which cell reproduce themselves. Two types of cell division- Somatic cell division/ Equational division/ mitosis Reproductive cell division/ reductional division/ meiosis. Both have different mechanisms and different goals.

33. How does cells reproduce? (By cell division- mitosis and meiosis ) After growing to an optimum size, the cell divides into daughter cells. Cells with nuclei have 46 chromosomes (23 pair) and divide by mitosis , a process that results in two new genetically identical daughter cells. 23 rd chromosome- Sex cells which takes place by meiosis. The period between two cell division is called cell cycle. Cell cycle (24 hours)- sequence of events where cell duplicates its genetic material  synthesizes substances essential for cell division  undergoes cell division  daughter cells. Cell cycle have two phases- Mitotic phase (M- Phase) and Interphase = MITOSIS. 33

34. INTERPHASE (Resting phase) It is the period between two mitotic phase. It is the longer phase that occurs in three stages: First gap phase (G 1 )- about 10 hours The cell grows in size and volume. Metabolically active phase for cell growth. 34

35. INTERPHASE Synthesis of DNA (S-Phase)- about 9 hours- The chromosomes replicates forming two identical copies of DNA. Therefore, following the S phase, the cell now has 92 chromatids i.e. enough DNA for two daughter cells and is nearly ready to divide by mitosis. Second gap phase (G 2 ) about 4 hours- Further growth and preparation for cell division. Synthesis of spindle fibres, RNA, cell organelles, ATP etc. Note- Mitosis- 1 hour 35

36. INTERPHASE G phase- Also called quiescent phase. It lies between interphase and M-phase. Certain cells do not divide or they divide when needed during cell injury, dead cells replacement. These cells do not enter S- phase and remain active in G - phase . They re-enter the cycle only when needed. 36

37. CELL CYCLE 37

38. MITOSIS- 1 hour karyokinesis – division of chromosome Cytokinesis- division of cytoplasm In somatic cells, each chromosome duplicates into two daughter cells which possess the same number of chromosomes as the parent cell. Therefore, it is also called EQUATIONAL DIVISION. 38 F ormation of daughter cells

39. MITOSIS - karyokinesis PROPHASE- First and longest phase. Divided into early prophase and late prophase EARLY PROPHASE- condensation of chromatin, formation of sister chromatids joint by centromere, membrane centrosome divides into two  two new centrosomes move away from each other to the two ends of the nucleus forming two poles . LATE PROPHASE- Assembly of microtubules and spindle fibres with the help of cytoplasmic proteins  disappearance of nuclear membrane, nucleolus and organelles like ER and golgi complex. 39

40. MITOSIS - karyokinesis METAPHASE (Middle phase): Complete condensation of chromosomes visible chromosomes  morphological study of chromosome can be done at this phase. chromosomes are arranged around the centre of the cell  they get attached to thread like structures of the centrosomes which are now at the two poles of the cell. Sister chromatids held together by a centromere now develops a disc shaped kinetochore (helps align the mitotic chromosomes at equatorial plane of the cell- metaphasic plate). Kinetochore of one sister chromatid of a chromosome is attached to the spindle fibres of one pole while the other sister chromatid of a chromosome is attached to the spindle fibres of another pole  facilitates the separation of the two sister chromatids. 40

41. MITOSIS - karyokinesis ANAPHASE (apart) Shortest phase the chromosomes now divide longitudinally into two equal parts. Movement of chromosomes move away from the equatorial plane towards the poles and get arranged around the centromeres. Separation of sister centromeres  formation of 2 daughter chromosomes. 41

42. MITOSIS - karyokinesis TELOPHASE (far/separate) Changes occurring are opposite to that of prophase. Daughter chromosomes at poles are enclosed by newly synthesized nuclear membrane. Reappearance of nucleolus, ER and golgi complex. The cell becomes narrower at the centre to facilitate division and the thread like structure disappear. The daughter cells contains 46 chromosomes. 42

43. MITOSIS - Cytokinesis Division of a cell’s cytoplasm and organelles into two identical cells is called cytokinesis. This process usually begins in late anaphase with the formation of a cleavage furrow, a slight indentation of the plasma membrane, and is completed after telophase. 43

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46. MEIOSIS It is a process of reproduction which occurs in higher animals including man . It is the final step in the gamete ( Spermatozoon and ovum) production . On fertilization, when the male and female gametes unite, the resulting zygote is diploid in number (because each gamete was haploid). Spermatozoon : It is the mature motile male sex cell which contains 23 chromosomes Ovum: It is the female reproductive cell which also contains 23 chromosomes. are also called gametes. Formation of zygote leads to the mixing of hereditary determinants or genes from the male and female. Unlike mitosis, meiosis involves two distinct cell divisions rather than one. Additionally, meiosis produces four daughter cells and not two , all different from the parent cells and from each other. 46

47. MEIOSIS MALE  TESTES  SPERMATOGONIUM FEMALE  OVARY  OOGONIUIM 47 Primary oocyte Primary spermatocyte Mitosis Meiosis Meiosis Egg cell (n) Sperm cell (n ) Zygote (2n)  completes human body CELL CYCLE Interphase ( preparation phase) G1 phase S phase G2 phase Meiosis ( Actual division ) M 1 2n n n n n n n M2 M 2

48. 48 MEIOSIS MEIOSIS-I MEIOSIS-II Karyokinesis -I cytokinesis Karyokinesis-I cytokinesis Prophase-I Metaphase-I Anaphase-I Telophase-I Prophase-II Metaphase-I Anaphase-II Telophase-II Leptotene Zygotene Pachytene Diplotene Diakinesis Thin, long thread like chromatin fibres condenses forming thick chromosomes. Pairing or synapsis of homologous chromosome, bivalent chromatids formation Further condensation, tetrad formation (4 chromatids), crossing over ( chiasmata - helps in exchange of genetic material) of a non-sister chromatids Disappearance of nuclear envelope, nucleoli, desynapsis (separation of homologous chromosome) occur. Terminalization - further condensation of bivalent chromosome, movement of chiasmata towards the end position of homologous chromosome.

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50. MEIOSIS First meiotic division: This stage produces two genetically different daughter cells. After DNA replication, each pair of chromosome is now four chromatids and they gather together into tight bundle due to which it becomes easier for them to exchange genes. This process is called crossing over. Following crossing over, the pairs of chromosomes then prepare for the first meiotic cell division and transfer of maternal and paternal chromosomes to either daughter cell is random. Each pair of chromosomes separates and one travels to each end of the cell, guided by a spindle, as in mitosis, producing two genetically unique diploid daughter cells. 50

51. MEIOSIS Second meiotic cell division: for a gamete to be produced, the amount of genetic material present in the two daughter cells following the 1 st meiotic division must be halved. This is accomplished by the 2 nd meiotic division. The centromeres separate and the two sister chromatids travel to opposite ends of the cell, which then divides. Each of the four haploid daughter cells now has only one chromosome from each original pair . Fusion with another gamete creates a zygote (fertilizes ovum), a diploid cell that can go on to grow and develop into a human being by mitosis. 51

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53. DETERMINATION OF SEX One pair of chromosomes from the father and one pair of chromosomes from the mother are sex chromosomes. These sex chromosomes determines the sex of the child. Females posses same chromosomes that is XX and male possess XY chromosome. one chromosome from each pair determines the sex of the child. If the child has X chromosome from both the mother and father, it is a female(XX). If the child has X chromosome from the mother and Y chromosome from the father then it is a male(XY). 53

54. CELL JUNCTIONS 54

55. CELL JUNCTIONS Cell junction is the connection between the neighboring cells or the contact between the cell and extracellular matrix. It is also called membrane junction . The intestinal epithelium and skin epidermis have a similar complement of cell–cell junctions. These cell–cell junctions form extracellular connections between adjacent cells and intracellular connections Its main functions are to : maintain homeostasis by regulating the structural integrity of the tissues help in the diffusion of ions, solutes, and microbes across the tissue, cell proliferation, and cell migration Cell junction are classified into three types a-Occluding junction (tight junction) b- Anchoring junction (desmosomes, hemi-desmosome, adherens junction) c-Communicating junction (gap junction) 55

56. Occluding Junction (Tight junction) A cell-cell junction that seals cells together in an epithelium in a way that prevents even small molecules from leaking from one side of the sheet to the other. Tight Junction/occluding junctions/ zonula occludens are the closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid. It is a type of junction complex present only in vertebrates. In mammals, the tight junction (TJ) is located at the apex of the lateral plasma membranes. The TJ encircles each cell, forming a proteinaceous seal that regulates the diffusion of ions and solutes between cells. The TJ is composed of two families of trans-membrane proteins, claudin and occludin. Claudin forms the characteristic TJ strands which generates a complex network of gaps or pores through which different ions and solutes diffuse. occludin may regulate the flux of large macromolecules across the intestinal TJ barrier 56

57. Function of Tight Junction Provides Strength and stability Acts as Selective permeable for ions. Claudin -16 in thick Junctions of Ascending Loop of Henle regulates the permeability or reabsorption of magnesium. Claudin-15 regulates the permeability of cations / anions by paracellular pathway. Actin turnover and actin myosin contraction , and immunoglobulin superfamily at the TJ also regulate TJ barrier function Microtubules associate with TJs through cingulin The TJ also plays a role in regulating cell proliferation and barrier function. 57

58. Anchoring/ adherens Junctions The adherens junction (AJ) initiates and maintains cell–cell adhesion , regulates the organization of the underlying actin cytoskeleton, and establishes a hub for cell signaling and regulation of gene transcription. AJ possess various cell adhesion molecules (CAMs) which are cell surface protein molecules that promotes cell- cell and cell-matrix interaction thereby is important for many normal biological processes -embryonic cell migration, immune system functions, wound healing. CAMs are involved in intracellular signaling pathways (primarily for cell death/survival, secretion etc.) STRUCTURE: have 3 main domains- The extracellular domain that allows one CAM to bind to another on an adjacent cell. The trans-membrane domain that links the CAM to the plasma membrane through hydrophobic forces. The cytoplasmic domain is directly connected to the cytoskeleton by linker proteins. 58

59. Anchoring/ adherens Junctions 59 The CAMs can be divided into 4 major families The cadherin superfamily The selectins The immunoglobulin superfamily and The integrins CADHERIN: E-cadherin is the main type of trans-membrane protein comprising the AJ and is engaged in CA 2+ -dependent trans-binding to a cadherin on the opposing cell surface. SELECTIN: They are expressed in the activated platelets and the endothelial cells . It has the ability to bind to the specific carbohydrate ligand. IMMUNOGLOBULIN SUPERFMAILY : Consists of more than 25 molecules. Important ones are- Intracellular Adhesion molecule-1 Intracellular adhesion molecule-2 Vascular cell adhesion molecule. Platelet endothelial cell adhesion molecule 1 INTEGRIN: Bind epithelial and muscle cells to the basal lamina and Allow platelets to stick to exposed collagen in a damaged blood vessel.

60. DESMOSOMES Also known as macula adherens is a cell structure specialized for cell-to-cell adhesion. Desmosome comprise of two sub-types- Desmoglein ( Dsg ) and Desmocollin ( Dsc ), are members of the cadherin family. Similar to classical cadherins, Dsg and Dcs contain five extracellular cadherin repeat domains. Dsg and Dcs interacts with two types of protein- plakoglobin (required for desmosome assembly by clustering Dsg / Dcs in plasma membrane)and plakophilin ( is required for recruitment of Dsc2 to the plasma membrane and forms a scaffolding complex which regulates the strength of interactions between desmoplakin and intermediate filaments to facilitate junctional integrity) . HEMIDESMOSOME- Hemidesmosomes look like half-desmosomes that attach cells to the underlying basal lamina. Hemidesmosomes utilizes desmopenetrin cell adhesion proteins, which are members of Integrin family. The integrin molecule attach to one of many multi-adhesive proteins such as laminin , resident within the extracellular matrix, thereby forming one of many potential adhesions between cell and matrix. 60

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63. Communicating Junction Cell junction which permit the intercellular exchange of substance are called communicating junction, these junction permit the movement of ions and molecules from one cell to another cell. a- Gap junction b- Chemical synapse Gap junctions- Clusters of intercellular channels that allow direct diffusion of ions between adjacent cells. At gap junctions, the intercellular space narrows from 25 nm to 3 nm. First discovered in myocardium and nerve It is present in heart, basal part of epithelial cell of intestinal mucosa etc. Junctional units are- Connexons - 6 connexins Connexon of one cell have allignment with connexon of other cells. Function of gap junction- channel passage the substance have molecular weight less than 1000. Exchange of chemical messenger between cells Rapid propagation of action potential from one cell to another cell. 63 Electron microscopy of gap junctions joining adjacent hepatocytes in the mouse. The gap junction (GJ) is seen as an area of close plasma membrane apposition

64. CHEMICAL SYNAPSE Chemical synapse is the junction between a nerve fibre and a muscle fiber or between two nerve fibre ,through which signals transmitted by the release of chemical transmitter. 64

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68. GENERAL PRINCIPLES OF CELL COMMUNICATION 68

69. CELL COMMUNICATION The process of sensing and responding to extrinsic signals is often termed cellular communication which are scientifically termed as ‘signal transduction’ or ‘signaling’. Extrinsic signals are- chemical messengers (hormones, growth factors, neurotransmitters), electrical impulses, mechanical forces, pH, heat and light. Cellular communication encompasses a vast range of- Extrinsic signals Intracellular signaling pathways Cellular response Cell communication occurs when extrinsic stimuli bind to receptors on their target cells. 69 Fig: Hypothetical cellular communication pathway

70. WHY DOES CELLS COMMUNICATE? Maintenance of homeostasis Control of division and cell death Adaptation to environmental conditions Control of development and growth Release and production of hormones and others regulatory molecules Regulation of metabolism 70

71. CELL SIGNALLING Cell signaling is a biological mechanism occurring in cells. It causes cell to receive the signals in response to their surrounding environment. By activating receptors, extrinsic signal trigger events that relay information within cells and ultimately cause cells to change their behavior. Receptors are highly specific or selective for their specific extrinsic stimuli. Activated receptors often have pleiotropic actions (the additional effect) which means they alter the activity of numerous cellular processes simultaneously . Therefore, the overall effect of switching various processes on or off determines the consequent change in cellular behavior. However, the aberrant (abnormal) cellular communication leads to conditions like cancer, diabetes, heart failure and neurological disorders. 71

72. STEPS INVOLVED IN CELL SIGNALLING Synthesis of the signaling molecule by the signaling cell Release of the signaling molecule by the signaling cell Transport of the signal to the target cell Binding of the signal with a specific receptor protein that brings conformational change Initiation of intracellular signal-transduction pathways by the activated receptor A change in cellular metabolism, function, structure, or development triggered immediately by the receptor-signal complex Usually deactivation of the receptor Removal of the signal , which usually terminates the cellular response 72

73. INTERCELLULAR SIGNALLING The transfer of information from one cell to another cell. Cells signals each other by direct contact with each other or by the release of a substance from one cell that is taken up another cell. This is important for cells to grow and function normally. TYPES OF INTERCELLULAR SIGNALLING: AUTOCRINE SIGNALLING PARACRINE SIGNALLING ENDOCRINE SIGNALLING JUXTACRINE SIGNALLING 73

74. AUTOCRINE SIGNALLING Autocrine signals target the cell itself . Sometimes autocrine cells can target cells close by if they are the same type of cells as the emitting cells. E.g. immune cells. Autocrine signaling is important during development, helping cells take on and reinforce their correct identities. 74

75. PARACRINE SIGNALLING These signals target cells in the vicinity of the emitting cell E.g. Neurotransmitters. Often, cells that are near one another communicate through release of chemical messengers (ligands that can diffuse through the space between the cells). 75

76. ENDOCRINE SIGNALLING They target the distant cell. When cells need to transmit signals over long distances, they often use the circulatory system as a distribution network for the messages they send. Signals that are produced in one part of the body and travel through the circulation to reach far-away targets are known as hormones. In human endocrine gland release one or more types of hormones, many of which are master regulators of development and physiology. 76

77. JUXTACELLULAR SIGNALLING Also called contact- dependent signaling as the signals target the adjacent cells. They are transmitted along cell membranes via protein or lipid components integral to the membrane. They are capable of affecting either the emitting cell or cells immediately adjacent cells. E.g. Notch signaling (during neurogenesis) , cadherin mediated adhesion etc. 77

78. SYNAPTIC SIGNALLING It is a special case of paracrine signaling (for chemical synapse) or juxtacrine signaling (for electrical synapse) between neurons and target cells. Signaling molecule interact with a target cell as a ligand to cell surface through its membrane or endocytosis for intracrine signaling. This generally results in the activation of second messengers, leading to various physiological effects. 78

79. INTRACELLULAR SIGNALLING PATHWAY ACTIVATION BY EXTRACELLULAR SIGNAL MOLECULE In most cases, the extracellular messenger molecule binds to a receptor at the outer surface of the responding cell. This interaction induces a conformational change in the receptor that causes the signal to be relayed across the membrane to the receptor’s cytoplasmic domain. Once it has reached the inner surface of the plasma membrane, there are two major routes by which the signal is transmitted into the cell interior, where it elicits the appropriate response. 79

80. INTRACELLULAR SIGNALLING PATHWAY ACTIVATION BY EXTRACELLULAR SIGNAL MOLECULE Transmission of molecular signals from the cell’s exterior to its interior. RECEPTORS Receptors are proteins associated with cell membranes or located within the cell. They recognize signaling molecules by binding to them. AGONIST: an agent which activates a receptor to produce an effect similar to that of the physiological action. INVERSE AGONIST: activates receptor to produce an effect in the opposite direction to that of the agonist. ANTAGONIST: prevents the action of an agonist on a receptor but does not have any effect of its own. 80 Extracellular signal molecule Receptor protein Plasma membrane of target cell Effector proteins Intracellular signal transduction

81. INTRACELLULAR SIGNALLING PATHWAY ACTIVATION BY EXTRACELLULAR SIGNAL MOLECULE 81 Some of the cell surface receptor-mediated cellular signaling pathways that operate in eukaryotic cells and some of the responses that these pathways elicit are depicted in the R.H.S figure. GPCR: G-protein coupled receptor IP 3 : inositol 1,4,5-triphosphate PIP 3 : phosphatidylinositol 3,4,5-triphosphate.

82. FUNCTIONS OF RECEPTORS To propagate regulatory signals from outside to within the effector cell when the molecular species carrying the signal cannot itself penetrate the cell membrane. To amplify the signal To integrate various extracellular and intracellular regulatory signal. 82

83. G-Protein coupled receptors (G-PCR) G protein-coupled receptors (GPCRs) are so named because they interact with G proteins (GTP- binding proteins) They have seven trans-membrane helical structures. The agonist binding site is located somewhere between the helices on the extracellular face while another recognition site is formed on the inner side of the structure of GPCR where it binds to G-protein. After binding, it either leads to activation of cAMP pathway (secondary messengers) which is possible when Adenylyl cyclase gets accumulated intracellularly or activation of IP 3 pathway ( mobilizes calcium from endoplasmic reticular depots. This pathway alters the function of many enzymes, ion channels, transcription factors and structural proteins to manifest as increases contractility/ impulse generation, relaxation, glycogenolysis etc. 83

84. INTRACELLULAR SIGNALING PATHWAY (G-PCR) 84

85. ION CHANNEL RECEPTOR They are cell surface receptor They are also called ligand gated ion channel. They enclose ion selective channels (for sodium- Na + , potassium-K + , calcium- Ca 2+ or chloride ions- Cl - ) within their molecules. When agonist binds the channel opens. It may lead to- depolarization/hyperpolarization/ changes in cytosolic ionic composition. 85

86. TRANSMEMBRANE ENZYME LINKED RECEPTOR This class of receptors are utilized primarily by peptide hormones. These receptors are made up of large extracellular domain connected through a single trans-membrane helical peptide chain to an intracellular subunit having enzymatic property. The enzyme generally present is protein kinase or guanylyl cyclase. Protein kinase phosphorylates tyrosine residues on the substrate proteins and are called receptor tyrosine kinase. 86

87. NUCLEAR RECEPTORS These receptors are class of proteins found within the cells that are responsible for sensing steroid and thyroid hormones and certain other molecules. In response, these receptors work with other proteins to regulate the expression of specific genes. Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes. 87 Nuclear receptor (glucocorticoid receptor) activation

88. 88 Thank you