PDQ PHYSIOLOGY D-glucoronic acid N-acetyl-D-glucosamine D-glucoronic acid N-acetyl-D-galactosamine HYALURONIC ACID (n< 50,000) ROITIN 4-SULFATE(n< 250 Nso N-acetyl-D-galactosamine DERMATAN SULFATE (n 250 HEPARIN (n=15-30) D-galactose N-acetyH-D-glucosamin Figure 1-8 Each of the glycosaminoglycans is formed by polymerization of a particular di- saccharide. The carboxyl lfate groups contribute to the highby charged polyanionic nature of glycosaminoglycans. Heparan sulfate is not shown. It resembles heparin in its disaccharide peats but differs in the number of acetyl-and sulfate groups n= the number of repeat units in each chain In many cases, ATP is used directly, but some reactions are powered by Guanosine triphosphate(GTP)is used in gluconeogenesis and protein Uridine triphosphate(UTP) is used in glycogen synthesis. ytosine triphosphate( CTP) is used in lipid synthesis. Inosine triphosphate(ITP)is used in several enzyme-catalyzed reactions A variety of enzymes promote transfer of the terminal energy-rich phosphate bond from ATP to these other triphosphates. Energy production Energy production involves the formation of the terminal phosphate bond in the ATP molecule. This happens most abundantly in mitochondria by oxidative phosphorylation when NADH and FADH,' are oxidized by electron flavin adenine
In many cases, ATP is used directly, but some reactions are powered by different nucleoside triphosphates: • Guanosine triphosphate (GTP) is used in gluconeogenesis and protein synthesis. • Uridine triphosphate (UTP) is used in glycogen synthesis. • Cytosine triphosphate (CTP) is used in lipid synthesis. • Inosine triphosphate (ITP) is used in several enzyme-catalyzed reactions. A variety of enzymes promote transfer of the terminal energy-rich phosphate bond from ATP to these other triphosphates. Energy Production Energy production involves the formation of the terminal phosphate bond in the ATP molecule. This happens most abundantly in mitochondria by oxidative phosphorylation when NADH and FADH2 ‡ are oxidized by electron 20 PDQ PHYSIOLOGY OH OH H H H O H O H H H O H CH2OH O COO– H NHCOCH3 O n OH OH H H H O H O H H H O H CH2OH O COO– H –O3SO NHCOCH3 O n OH OH H H H O H O H H H O H CH2OH O COO– H –O3SO NHCOCH3 O n OH OH H H H O H O H H H O H CH2OH O COO– H O n OH D-glucoronic acid N-acetyl-D-glucosamine HYALURONIC ACID (n < 50,000) CHONDROITIN 4-SULFATE (n < 250) D-glucoronic acid N-acetyl-D-galactosamine L-iduronic acid N-acetyl-D-galactosamine DERMATAN SULFATE (n < 250) OH H HNSO3 H D-glucoronic acid N-sulfo-D-glucosamine HEPARIN (n=15-30) OH OH H H H O H H H H O H CH2OH O H NHCOCH3 O n D-galactose N-acetyl-D-glucosamine KERATAN SULFATE (n=20-40) O CH2OH – Figure 1–8 Each of the glycosaminoglycans is formed by polymerization of a particular disaccharide. The carboxyl and sulfate groups contribute to the highly charged polyanionic nature of glycosaminoglycans. Heparan sulfate is not shown. It resembles heparin in its disaccharide repeats but differs in the number of acetyl- and sulfate groups. n = the number of repeat units in each chain. ‡NADH = reduced nicotinamide adenine dinucleotide; FADH2 = reduced flavin adenine dinucleotide
Chapter 1 General Physiologic Processes 21 transport through the respiratory chain when oxygen is freely available. The substrates NADH and FADH, are produced in the Krebs cycle(citric acid cycle), and its substrate is acetyl Co-A. Acetyl Co-A can be formed by differ- ent pathways from the three dietary sources: carbohydrates, proteins, and fats hydrates are broken down to glucose and other sI Glucose is converted to two pyruvate molecules by the steps of glycol- ysis. Pyruvate is converted to acetyl Co-A by the enzyme pyruvate dehy Proteins are broken down to their constituent amino acids. Amino acids are then degraded by the removal of the alpha-amino group in a process called transamination. The resulting carbon skeleton is converted into one of only seven metabolic intermediates. Of these seven, four are interme- diates in the Krebs cycle, two are readily converted to acetyl Co-A(pyru- vate and acetoacetyl Co-A), and the remaining one is acetyl Co-A itself. Dietary fats are mostly triglycerides, and they are broken down to glyc erol (10% of the triglyceride molecule)and fatty acids(90%). Glycerol is rapidly converted to glucose, and the fatty acids are first transferred from the cytosol to the mitochondria and then broken down by beta-oxidation two carbon atoms at a time, to acetyl Co-A Cell Cycle Regulation of the Cell cycle and Cell Growth Cells that are not destined to replicate are in the go state. Those that will replicate are in one of the phases of the cell cycle(Figure 1-9). This cycle consists of interphase(Gi+ S+ G2), during which a newly formed cell becomes a parent cell by doubling its content, and mitosis(M)(see Figure during which a parent cell becomes two daughter cells, each with a complete set of chromosomes Regulation of the cell cycle is critically dependent on the cyclin family of proteins. Mitosis is initiated when cyclins combine with p34 e to form dc2-kinase that, in turn, phosphorylates relevant target proteins. Cell growth is regulated by extracellular protein growth factors that ini tiate receptor-mediated intracellular cascades for gene transcription and cell cycle control CELL-TO-CELL COMMUNICATION Gap Junction Gap junctions are regions where a uniform, narrow gap of 2 to 3 nm between the membranes of two neighboring cells is"bridged" by an assembly of six rods(2.5 nm in diameter, 7.5 nm in length). The rods are formed by a group
transport through the respiratory chain when oxygen is freely available. The substrates NADH and FADH2 are produced in the Krebs cycle (citric acid cycle), and its substrate is acetyl Co-A. Acetyl Co-A can be formed by different pathways from the three dietary sources: carbohydrates, proteins, and fats. • Carbohydrates are broken down to glucose and other simple sugars. Glucose is converted to two pyruvate molecules by the steps of glycolysis. Pyruvate is converted to acetyl Co-A by the enzyme pyruvate dehydrogenase. • Proteins are broken down to their constituent amino acids. Amino acids are then degraded by the removal of the alpha-amino group in a process called transamination. The resulting carbon skeleton is converted into one of only seven metabolic intermediates. Of these seven, four are intermediates in the Krebs cycle, two are readily converted to acetyl Co-A (pyruvate and acetoacetyl Co-A), and the remaining one is acetyl Co-A itself. • Dietary fats are mostly triglycerides, and they are broken down to glycerol (10% of the triglyceride molecule) and fatty acids (90%). Glycerol is rapidly converted to glucose, and the fatty acids are first transferred from the cytosol to the mitochondria and then broken down by beta-oxidation, two carbon atoms at a time, to acetyl Co-A. Cell Cycle Regulation of the Cell Cycle and Cell Growth Cells that are not destined to replicate are in the G0 state. Those that will replicate are in one of the phases of the cell cycle (Figure 1–9). This cycle consists of interphase (G1 + S + G2), during which a newly formed cell becomes a parent cell by doubling its content, and mitosis (M) (see Figure 1–9), during which a parent cell becomes two daughter cells, each with a complete set of chromosomes. Regulation of the cell cycle is critically dependent on the cyclin family of proteins. Mitosis is initiated when cyclins combine with p34cdc2 to form cdc2-kinase that, in turn, phosphorylates relevant target proteins. Cell growth is regulated by extracellular protein growth factors that initiate receptor-mediated intracellular cascades for gene transcription and cell cycle control systems. CELL-TO-CELL COMMUNICATION Gap Junctions Gap junctions are regions where a uniform, narrow gap of 2 to 3 nm between the membranes of two neighboring cells is “bridged” by an assembly of six rods (2.5 nm in diameter, 7.5 nm in length). The rods are formed by a group Chapter 1 General Physiologic Processes 21
PDQ PHYSIOLOGY START Figure 1-9 Schematic of the cell replication cycle. The life of the cell begins in G, and pr gresses in response to intra-and extracellular signals. G1="Gap 1. " Cell growth occurs here cell determine adequacy of cell size and quality of the extracellular environme teins, the cyclins, is synthesized; M=the period of mitosis. Mitosis is divided metaphase, anaphase, telophase, and cytokinesis, each characterized by a particular arrange- become visible as paired chromatids that are tubules of each aster begin to capture randomly moving chromosomes, and the two centrosomes begin to move toward opposite sides of the nucleus. The disintegrate in late prophase, and such breakdow Metaphase: All of the chromosomes become attached at their centromere to the microtubules of the spindle and become aligned across the middle of the spindle, each pair of about 30 minuter naphase: Chromatids separate in unison and begin to move toward the spindle poles. They complete the migration to the poles within about 5 minutes Telophase: The chromosomal condensations at each pole fade and start reverting to chro- v nuclear membranes form, and the parent cell begins the processes Cytokinesis: A constriction ring of actin filaments and myosin forms around the elongated cell. The cytoplasm then cleaves The chromosomes continue to dis- perse, and a nucleolus reappears in each daughter cell
22 PDQ PHYSIOLOGY G2 S prophase metaphase anaphase telophase cytokinesis G1 M START Figure 1–9 Schematic of the cell replication cycle. The life of the cell begins in G1 and progresses in response to intra- and extracellular signals. G1 = “Gap 1.” Cell growth occurs here. The brief interval labeled “START” represents a time at which certain components within the cell determine adequacy of cell size and quality of the extracellular environment; S = Replication of DNA within the nucleus; G2 = “Gap 2.” A quiescent period during which a group of proteins, the cyclins, is synthesized; M = the period of mitosis. Mitosis is divided into prophase, metaphase, anaphase, telophase, and cytokinesis, each characterized by a particular arrangement and location of the genetic material as shown: Prophase: Condensed chromosomes first become visible as paired chromatids that are attached to each other at the centromere with its associated kinetochore. Microtubules of each aster begin to capture randomly moving chromosomes, and the two centrosomes begin to move toward opposite sides of the nucleus. The nuclear envelope begins to disintegrate in late prophase, and such breakdown defines the beginning of prometaphase. Prometaphase lasts about 10 minutes and is followed by metaphase. Metaphase: All of the chromosomes become attached at their centromere to the microtubules of the spindle and become aligned across the middle of the spindle, each pair of sister chromatids being held by oppositely directed microtubules. Metaphase lasts about 30 minutes. Anaphase: Chromatids separate in unison and begin to move toward the spindle poles. They complete the migration to the poles within about 5 minutes. Telophase: The chromosomal condensations at each pole fade and start reverting to chromatin, new nuclear membranes form, and the parent cell begins the processes of cytokinesis. Cytokinesis: A constriction ring of actin filaments and myosin forms around the midbody of the elongated cell. The cytoplasm then cleaves. The chromosomes continue to disperse, and a nucleolus reappears in each daughter cell
Chapter 1 General Physiologic Processes of proteins called the connexins. They are not continuous across the gap but align themselves at a slight angle so as to form a connexon, a formation that reates a 1-to 1.5-nm pore between the two cells( Figure 1-10). The angle of the tilt may be important for modulation of conductivity across the junction Gap junctions are regions of permeation for small molecules and ions less than 1, 500 to 2, 500 kDa in size. This includes all intracellular ions and second messengers. Neutral molecules move across more easily than do neg- atively charged species The total number of gap junctions between two cells is increased by cyclic adenosine monophosphate(cAMP). In addition, conductance of dividual gap junctions is ncreased by (1)diminished [H*Ji and(2)elevated [cAMP] and its con- sequent protein kinase A-dependent connexin phosphorylation; s and decreased by(1)elevated protein kinase C-dependent connexin phos phorylation, (2)cell depolarization, (3)elevated [Hi(4)elevated tyro sine kinase-dependent phosphorylation, and(5)markedly elevated [Ca*] cal uncoupling of neighboring cell Reduction of gap junction conductance leads to electrical and che Synapses Synapses are specialized appo between presynaptic and postsynaptic membranes for the purpose ormation transfer between a nerve and another cell. The two synapsing cells do not touch physically but are separated This inhibitory effect of cAMP on gap junction conductance is seen in some cells In oth ers, elevated cAMP an kinase A-dependent connexin phosphorylation have the opposite effect. 1-10 Schematic of half a gap junction between the adjoining plasma membranes of lls. They are 2 to 3 nm apart and are bridged by the slightly tilted rods of connexins, a of gap junction proteins. Only three rods are shown in each cell. Normally, groups of six themselves in a rosette that forms a central pore
of proteins called the connexins. They are not continuous across the gap but align themselves at a slight angle so as to form a connexon, a formation that creates a 1- to 1.5-nm pore between the two cells (Figure 1–10). The angle of the tilt may be important for modulation of conductivity across the junction. Gap junctions are regions of permeation for small molecules and ions less than 1,500 to 2,500 kDa in size. This includes all intracellular ions and second messengers. Neutral molecules move across more easily than do negatively charged species. The total number of gap junctions between two cells is increased by cyclic adenosine monophosphate (cAMP). In addition, conductance of individual gap junctions is • increased by (1) diminished [H+]i and (2) elevated [cAMP] and its consequent protein kinase A–dependent connexin phosphorylation;§ and • decreased by (1) elevated protein kinase C–dependent connexin phosphorylation, (2) cell depolarization, (3) elevated [H+]i, (4) elevated tyrosine kinase–dependent phosphorylation, and (5) markedly elevated [Ca++]i . Reduction of gap junction conductance leads to electrical and chemical uncoupling of neighboring cells. Synapses Synapses are specialized appositions between presynaptic and postsynaptic membranes for the purpose of information transfer between a nerve and another cell. The two synapsing cells do not touch physically but are separated Chapter 1 General Physiologic Processes 23 Figure 1–10 Schematic of half a gap junction between the adjoining plasma membranes of two cells. They are 2 to 3 nm apart and are bridged by the slightly tilted rods of connexins, a group of gap junction proteins. Only three rods are shown in each cell. Normally, groups of six arrange themselves in a rosette that forms a central pore. §This inhibitory effect of cAMP on gap junction conductance is seen in some cells. In others, elevated cAMP and protein kinase A–dependent connexin phosphorylation have the opposite effect
PDQ PHYSIOLOGY by a narrow cleft. While electrical synapses(gap junctions)are known to occur in the nervous system, most synapses are regions of chemical information transfer. The presynapticelement synthesizes and releases a chemical substance named a neurotransmitter or a neuropeptide, and this acts mostly on the postsynaptic element by way of postsynaptic membrane receptors. In some cases, the released chemical may also act on membrane receptors in the presy- haptic element as a strategy for modulating transmitter(or peptide)release. Electrical communication Membrane potentials The concentration differences for several ion species distributed on the two sides of the plasma membrane cause healthy human cells to have an electri- cal life, the gross manifestation of which can be measured as a difference in voltage between the inside and outside of the cell. This voltage is called the membrane potential. Excitable cells display a resting membrane potential when they are at electrical rest and an action potential when they are excited. Balance of forces across cell surface membranes. The presence of conducting ion channels and some leakage through the lipid bilayer make the plasma membrane a leaky barrier between two regions of generally large differences in ion concentrations. When an ion species moves across the plasma membrane down its concentration gradient, then an opposing transmembrane gradient in electrical potential is created. As a result, ion movement down a concentration gradient will not continue to the point where the concentration difference has been abolished. Instead, passive ion (net)transport across the plasma membrane stops when the force arising from the remaining concentration gradient is balanced by the opposing force arising from the gradient in electrical potential As a result, electrically resting cells exist in a steady state, in which each of the ion species is maintained at a concentration difference across the plasma membrane by an equal and opposite electrical force. It is possible to calculate for any ion species the electrical force that would be required to provide an exact counterbalance for its steady-state concentration gradient. That electrical force is named the ion equilibrium potential or the Nernst potential for that ion lon equilibrium potential. Definition. The ion equilibrium potential (Eion )or the Nernst potential of an ion species is the electrical driving force that would (1) be equal in magnitude but opposite in direction to the driving force represented by the concentration gradient and (2)prevent net passive transport of that ion species Any ion species would stop to move passively across the plasma mem- brane and down its concentration gradient once the potential difference across the membrane is equal to e
by a narrow cleft. While electrical synapses (gap junctions) are known to occur in the nervous system, most synapses are regions of chemical information transfer. The presynaptic element synthesizes and releases a chemical substance named a neurotransmitter or a neuropeptide, and this acts mostly on the postsynaptic element by way of postsynaptic membrane receptors. In some cases, the released chemical may also act on membrane receptors in the presynaptic element as a strategy for modulating transmitter (or peptide) release. Electrical Communication Membrane Potentials The concentration differences for several ion species distributed on the two sides of the plasma membrane cause healthy human cells to have an electrical life, the gross manifestation of which can be measured as a difference in voltage between the inside and outside of the cell. This voltage is called the membrane potential. Excitable cells display a resting membrane potential when they are at electrical rest and an action potential when they are excited. Balance of forces across cell surface membranes. The presence of conducting ion channels and some leakage through the lipid bilayer make the plasma membrane a leaky barrier between two regions of generally large differences in ion concentrations. When an ion species moves across the plasma membrane down its concentration gradient, then an opposing transmembrane gradient in electrical potential is created. As a result, ion movement down a concentration gradient will not continue to the point where the concentration difference has been abolished. Instead, passive ion (net) transport across the plasma membrane stops when the force arising from the remaining concentration gradient is balanced by the opposing force arising from the gradient in electrical potential. As a result, electrically resting cells exist in a steady state, in which each of the ion species is maintained at a concentration difference across the plasma membrane by an equal and opposite electrical force. It is possible to calculate for any ion species the electrical force that would be required to provide an exact counterbalance for its steady-state concentration gradient. That electrical force is named the ion equilibrium potential or the Nernst potential for that ion. Ion equilibrium potential. Definition. The ion equilibrium potential (Eion) or the Nernst potential of an ion species is the electrical driving force that would (1) be equal in magnitude but opposite in direction to the driving force represented by the concentration gradient and (2) prevent net passive transport of that ion species. Any ion species would stop to move passively across the plasma membrane and down its concentration gradient once the potential difference across the membrane is equal to Eion. 24 PDQ PHYSIOLOGY