Receptors
Specific receptor molecules that are present on the outer surface of the membrane of target cells interact with physiological ligands, such as lipoproteins, immunoglobulins, peptide hormones, and neurotransmitters; these are fin messengers. The activated receptor then interacts with an enzyme system within the cell that produces second messengers, such as cyclic adenosine monophosphate (CAMP), inositol triphosphate (IP3) and diacylglycerol (DAG). These in turn trigger a chain of intracellular reactions that eventually leads to the usual response of the cell to its physiological ligand. The number of receptors on a cell membrane increases and decreases in response to stimuli. Thus, for example, if a neurotransmitter or hormone (first messenger) is present in excess, the number of active receptors decreases (down-regulation); if there is a deficiency the number of receptors increases (up-regulation). When activated, these receptors initiate the release of the second messengers via GTP-binding proteins (G protein).
G proteins
These regulatory proteins translate a signal to a biological event within a cell. GTP is the guanosine analogue of ATP When stimulated the G protein exchanges GDP for GTP. There are many different G proteins, and the heterotrimeric ones are made up of a, 13 and y subunits. The a subunit is bound to GDP and separates from the 11 and y subunits when GDP is exchanged for GTP. This separation of the a subunit brings about the biological effects within the cell. These heterotruneric G protein-coupled receptors span the cell membrane seven times (serpentine receptors) and many have been isolated (e.g. 13, adrenergic receptor). Defective or damaged receptors can lead to disease states; examples are the acetylcholine receptor in myasthenia gravis, and the low-density lipoprotein (LDL) receptor in familial hypercholesterolaemia.
Second messengers
these can alter the function of the cell in the short term in many ways. For example, they can trigger exocytosis, alter enzyme function or induce transcription of many
genes. They do this by activating protein kinases which catalyse the phosphorylation of, for example, tyrosine or serine residues in proteins.
Differential domains
Certain areas of the cell membrane are structurally different; for example, the low-density lipoprotein (LDL) receptor lies in an evagination or 'pit'. This pit is coated with heavy and light chains of clathrin. These coated pits become detached and form coated vesicles (endocytosis). Another example is the absorptive cell which has a characteristic brush border with microvilli containing enzymes for digestion.
Cell-to-cell recognition and communication
At certain points the cell •membrane is joined to its neighbouring cell and intercellular channels allow diffusion of ions or small molecules .
Cytoplasm
The cytoplasm contains many specialized organelles that serve different functions. These include storage of sub-stances (e.g. glycogen and lipids), the synthesis of essential substances (e.g. amino acids, fatty acids, monosaccharides), the metabolism of these substances, and protein synthesis and
translation. Microtubules are cylindrical structures formed from the protein tubulin; they help to maintain the structure of the cells and form channels for communi-cation between the subcellular organelles. Endoplasmic reticulum This is a network of tubules throughout the cytoplasm from the nucleus to the cell membrane. It is divided into:
• the nuclear membrane surrounding the nucleus and controlling traffic in and out of the nucleus
• the rough endoplasmic reticulum (RER), which is lined by ribosomes that synthesize proteins
• the smooth ettdoplasmie refit-W.1in (SER), consisting of tubules and vesicles containing microsomes.
Endoplasmic reticulum is involved in the processing of secretory proteins. Some contain enzyme systems (e.g. mixed-function oxygenases, including cytochrome P450) that hydroxylate hydrophobic compounds, making them more soluble and therefore easier to metabolize (e.g. vitamin 1)) or eliminate (e.g. drugs).
The Golgi apparatus
This consists of channels or vesicles. Functions include modification and packaging of secretory proteins, transport of lysosomal enzymes to lysosornes, and storage. The Golgi apparatus acts as a focal point for the complex intracellular traffic that takes place between all of the subcellular components.
Mitochondria These consist of double membranes with an extensively infolded inner membrane, forming cristae. There are several hundred per cell. They contain enzymes responsible for oxidative phosphorylation, the citric acid cycle, the electron-transport chain and ATP synthesis. ATP is the principal source of energy in man. Mitochondria contain their own DNA, and teleologically they were autonomous micro-organisms that became incorporated into the eukarytic cell. Proteins of the oncogene family 13r/-2 are found in the outer membrane of the mitochondria where they inhibit or facilitate apoptosis .
Lysosomes
These contain digestive enzymes, mostly acid hydrolases, capable of digesting many constituents of cells and tissues. The substrates can enter the lysosome directly or via the Golgi apparatus. Lysosomes are involved in:
• the killing and digesting of infective agents by polymorphs and macrophages • removal of unwanted cells during embryonic development
• disposal of excess secretory products in glandular cells
• osteoclastic remodelling of bone by secreted enzymes. Lysosomal proteolysis is not quantitatively important in the normal turnover of most cellular proteins. Most are de-graded by a multienzymatic process that requires ATP. The
proteins are repeatedly linked to a small protein co-factor, ubiquitin, via their lysine residues. These ubiquitin conju-gated proteins which contain five or more ubiquitin mole-cules are rapidly degraded by a large proteolytic complex, the 26S proteasome. This ubiquitin—proteasome pathway is capable of selectively degrading most cell proteins.
The cytoskeleton
This consists of a complex network of structural elements which determine the shape of the cell, its ability to move and to respond to external stimuli. The major components are microtubules, intermediate filaments and microfilaments.
• Microtubules. These are made up of two protein subunits a and ft tubulin (50 kDa) and are continuously changing length. They form a 'highway' for motor proteins to move up and down the cell. Thus if an organelle is attached to a motor protein it can rapidly travel through the cytoplasm. There are two motor microtubule-associated proteins (MAP) — dynein and kinesin — allowing antegrade and retrograde movement. Dynein is also responsible for the beating of cilia. During interphase the microtubules arc rearranged by the microtubule organizing centre (MTOC), which consists of centrosomes containing tubulin and provides a structure on which the daughter chromosomes can separate. Another protein involved in the binding of organelles to microtubules is the cytoplasmic linker protein (CLIP). The intracellular position of the Golgi apparatus also involves microtubules. Drugs that disrupt the microtubule assembly (e.g. colchicine and vinblastine) affect the positioning and morphology of the organelles (Golgi apparatus and mitochondria). The anticancer drug paclitaxel causes cell death by binding to micro-tubules and stabilizing them so much that organelles cannot move, and thus mitotic spindles cannot form.
• Intermediate _filaments. These form a network around the nucleus and extend to the periphery of the cell. They make cell-to-cell contacts with the adjacent cells via desmosomes. Their function is uncertain but they may have a structural role.
• Microfilaments. Muscle cells contain a highly ordered structure of actin (a globular protein, 42-44 kDa) and myosin filaments which form the contractile system. These filaments are also present throughout the non-muscle cells as truncated myosins (e.g. myosin 1), in the cytosol (forming a contractile actomyosin gel), and beneath the plasma membrane. Cell movement is mediated by the ancorage of actin filaments to the plasma membrane and these filaments control the organization and shape of the cell.
Intracellular calcium and calcium-binding proteins
Calcium within the cell plays a major role in signalling. Most of the calcium is bound by the endoplasmic reticulum and by the other organdies. Calcium enters the cell by voltage-gated Ca2+ channels (activated by depolarization) and ligand-gated channels (activated by hormones and neurotransmitters). Ca2*-H*-ATPase pumps calcium ions out of the cell in exchange for hydrogen ions. Second messengers frequently act by increasing cytoplasmic calcium concentration. There are many calcium-binding proteins, such as troponin (involved in contraction of skeletal muscle), calmodulin and calbindin. Calmodulin, by binding Ca2÷, activates many calmodulin-dependent kinases, such as myosin light-chain kinase (which phosphorylates myosin), phosphorylasc kinase (activates phosphorylation), and calcineurin (which inactivates calcium channels). Calmodulin kinases are also involved with synaptic function, activating T cells, and can be inhibited by immunosuppressants. Calbindin binds and transports calcium ions across membranes.
The nucleus
A nucleus is present in all eukaryotic cells that divide. It contains the cell's genome, consisting of DNA and all the apparatus for replication and transcription into RNA. When the cell is not dividing, the nuclear envelope — consisting of an outer and an inner membrane — separates it from the cytoplasm. The outer membrane is continuous with the endoplasmic reticulum. A nucleolus (rich in RNA) is present in most nuclei, and nucleoli are the site of synthesis for ribosomes. There are two types of cell division — meiosis and mitosis. In meiosis, which occurs only in germ cells, the chromosome complement is halved (haploid) and, at fertilization, the union of two cells restores the full complement of 46 chromosomes. Mitosis occurs in dividing cells after fertilization, and results in two identical daughter cells. It is only during cell division that chromosomes become visible.
The cell cycle
Regulation of the cell cycle is complex. Cells in the quiescent GO phase (G, gap) of the cycle are stimulated by the receptor-mediated actions of growth factors (e.g. EGF, epithelial growth factor; PDGF, platelet-derived growth factor; IGF, insulin growth factor) via intracellular second messengers. Stimuli are transmitted to the nucleus where they activate transcription factors and lead to the initiation of DNA synthesis, followed by mitosis and cell division. Cell cycling is modified by the cyclin family of proteins which activate (by phosphorylation via kinases) proteins involved in DNA replication. Thus from GO the cell moves on to G1 (gap 1) when the
chromosomes are prepared for replication. This is followed by the synthetic (S) phase, when the 46 chromosomes are duplicated into chromatids, followed by another gap phase (G2) which eventually leads to mitosis (M). Cytokines (e.g. interferon) bind to receptors on target cells, causing the formation of protein complexes that are transferred to the nucleus. These receptors are part of a signalling complex (the JAK-STAT pathway) made up of JANUS kinases (JAK) and signal transducers and activators of transcription (STATs). Binding of interferon brings the JANUS kinases close to each other. They, the receptor chain and the STATs are activated by phosphorylation. The STAT dimer is transferred to the nucleus where it binds to regulatory DNA elements, thereby activating the genes that encode for the protein mediators produced by interferon stimulation.
Intercellular connections
There are two types of junction between cells, tight junctions and gap junctions.
Tight junctions
These (zonula occludens) hold cells together. They are at the apical margins of epithelial cells (e.g. intestinal and renal cells) and form a barrier to the movement of ions and solutes across the epithelium, although they can be variably 'leaky' to certain solutes. The zonula adherens is continuous on the basal side of cells, it contains cadherins, and is the major site of the attachment of intracellular microfdaments. Inter-mediate filaments attach to desmosomes, which are apposed areas of thickened membranes of two adjacent cells.
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