TAX 1973-1985 Q & A (student_s answers (not of any author).docx
cellular Transport and Signalling Student_s Copy
-
Upload
filchibuff -
Category
Documents
-
view
44 -
download
9
description
Transcript of cellular Transport and Signalling Student_s Copy
SAN BEDA COLLEGE OF MEDICINE Cellular Transport and Signaling BY Julianne Lopez, MD-MBA
SAN BEDA COLLEGE OF MEDICINE Page 1 of 6 Female Reproductive Physiology BY Julianne Lopez, MD-MBA
Cellular Transport and Signaling by Julianne Lopez, MD-‐MBA [email protected] 09178520849
Cellular Transport and Signaling EDUCATIONAL OBJECTIVES At the end of the 4-‐hour lecture, the future Bedan Doctor must be able to: • Illustrate the fluid-‐mosaic model of cell membranes • Describe the types of membrane transport.
o Differentiate between active and passive transport. o Describe features of the types of passive transport and
give their mechanisms. ! Simple diffusion ! Facilitated diffusion ! Osmosis
o Name and give features of the types of active transport. ! Primary active transport ! Secondary active transport
o Explain, using specific examples, the difference between primary and secondary active transport.
o Explain the importance and characteristics of carrier-‐mediated transport. ! Stereospecificity ! Competition ! Saturation
• Describe the modes of cell communication and signaling. o Describe the mechanisms of cellular communication
and regulation. ! Endocrine ! Neurocrine ! Paracrine ! Autocrine ! Juxtacrine
o Discuss the role of receptor proteins in cell signaling. o Name the types of signal transduction pathways.
! G-‐Protein mediated ! Second Messenger – dependent ion channels ! Second Messenger – dependent protein kinases
• Calmodulin dependent protein kinases • Cyclic AMP – dependent protein kinases • Atrial Natriuretic Peptide Receptor – guanylyl
cyclases
Cellular Membranes Cellular membranes (structure and composition) -‐ also called plasma membrane -‐ a thin, pliable, elastic structure that envelops the cell -‐ 7.5 to 10 nm thick -‐ composition:
FLUID MOSAIC MODEL:
-‐ primarily composed of a ___________ and ___________ -‐ phospholipid BILAYER
-‐ Mosaic " within the phospholipid bilayer are many
different types of embedded proteins and cholesterol molecules
-‐ Fluid "the embedded molecules can move sideways throughout the membrane, meaning the membrane is not solid, but more like fluid o Fluidity of the membrane is determined by
temperature and lipid composition ! Temperature: the higher the temperature, the
more fluid the membrane ! Lipid composition: presence of unsaturated
fatty acyl chains (double bond " “kink”) increases membrane fuidity
LIPID component of cell membrane: -‐ lipid bilayer -‐ composed of phospholipid molecules (major lipids of the
plasma membrane) -‐ phospholipids = ______________ backbone (hydrophilic,
charged, polar head) + 2 ___________ (hydrophobic, uncharged, nonpolar tail) o because it has a hydrophilic and hydrophobic end, a
phospholipid molecule is considered ___________ -‐ impermeable to water soluble substances
(_________________________________) -‐ permeable to lipid soluble substances
(_________________________________) -‐ cholesterol molecules is a critical component of the bilayer
o also amphipathic o contribute to the fluidity of the membrane o prevents the hydrophobic chains from packing too
closely together o stabilize the membrane at normal body temperature
-‐ glycolipids
o 2 fatty acyl chains linked to polar head groups that consist of carbohydrates
o also amphiphatic
55% 25%
13% 4% 3% protein
phospholipids
cholesterol
other lipids
carbohydrates
SAN BEDA COLLEGE OF MEDICINE Cellular Transport and Signaling BY Julianne Lopez, MD-MBA
SAN BEDA COLLEGE OF MEDICINE Page 2 of 6 Female Reproductive Physiology BY Julianne Lopez, MD-MBA
Protein Component of Cell membranes -‐ may either be integral or peripheral Integral membrane proteins -‐ embedded in, and anchored to, the cell membrane by
hydrophobic interactions -‐ some integral proteins are ______________________ (span the
lipid bilayer one or more times), thus are in contact with both ECF and ICF
-‐ some integral proteins are embedded but do not span it -‐ examples: ligand-‐binding receptors (for hormones or
neurotransmitters), transport proteins (i.e. Na+-‐K+ ATPase), pores, ion channels, G protein-‐coupled receptors
Peripheral membrane proteins -‐ are not embedded in the membrane -‐ are not covalently bound to cell membrane components
(loosely attached by _________________________________) -‐ attached to either the intracellular or extracellular side of
the cell membrane -‐ example: ankyrin – a peripheral membrane protein that
anchors the sytoskeleton of red blood cells to an integral membrane transport protein, the CL-‐HCO3 exchanger
Transport Across Membranes General Overview:
Notes:
Simple diffusion:
-‐ process by which molecules move spontaneously from an
area of high concentration to one of low concentration -‐ occurs as a result of random thermal motion of molecules
-‐ only form of transport that is NOT carrier-‐mediated -‐ occurs down an electrochemical gradient (“_________________”)
(meaning no energy expenditure), therefore, does NOT require metabolic energy and is considered PASSIVE
-‐ can be measured using the following equation (assuming a nonelectrolyte it is uncharged):
J = -‐PA (C1 – C2)
Where: J = flux (flow) (mmol/sec) P = permeability (cm/sec)
A = area (cm2) C1= concentration1 (mmol/L) C2= concentration2 (mmol/L)
-‐ Concentration Gradient (C1 – C2)
o The __________________________________ across the membrane is the DRIVING FORCE for net diffusion
o The larger the difference in solute concentration
between the 2, the greater the driving force, greater net diffusion
o What happens if 2 solutions are equal? Answer:
-‐ Permeability: describes the ease with which a solute diffuses through a membrane
P = KD Δx
Where:
transport across
membranes
simple diffusion
carrier-‐mediated transport
facilitated diffusion
active transport
primary secondary
SAN BEDA COLLEGE OF MEDICINE Cellular Transport and Signaling BY Julianne Lopez, MD-MBA
SAN BEDA COLLEGE OF MEDICINE Page 3 of 6 Female Reproductive Physiology BY Julianne Lopez, MD-MBA
P = permeability K = partition coefficient D = Diffusion coefficient X = membrane thickness
Factors affecting permeability:
Partition coefficient (K) o by definition, describes the solubility of a solute in oil
relative to its solubility in water ! the greater the relative solubility in oil, the higher
the partition coefficient, the more easily the solute can dissolve in the cell membrane’s lipid bilayer
o Predict: ! Non polar solutes: soluble in oil " _________________
_________________ ! Polar solutes: insoluble in oil
__________________________________ o Can be measured by adding the solute to a mixture of
olive oil and water then measuring its concentration in the oil phase relative to its concentration in water
K = concentration in olive oil concentration in water
Diffusion coefficient (D) o it is defined by the stokes-‐einstein equation
D = KT 6πrη
Where:
D = diffusion coefficient K = Boltzmann’s constant
o it correlates _________________with the molecular radius of the solute and viscosity of the medium ! Predict:
Small solutes " _________________diffusion coefficients " __________________________________ Viscous solutions " _________________ diffusion coefficients " __________________________________
Membrane thickness (x) o the thicker the cell membrane, the greater the distance
the solute must diffuse and the lower the rate of diffusion, therefore, membrane thickness and rate of diffusion is _________________________________________________
-‐ Surface Area (A) o The greater the SA, the _________________ the rate of
diffusion, therefore, it is _________________ proportional to one another
Diffusion of electrolytes -‐ implications:
1. The potential difference across the membrane will alter the rate of diffusion of a charged solute / electrolyte
2. When a charged solute diffuses down a concentration gradient (from higher concentration to lower concentration) that diffusion can itself generate a potential difference across a membrane called __________________________________
Carrier Mediated Transport -‐ facilitated diffusion, primary active transport and secondary
active transport all involve integral membrane proteins and are considered carrier-‐mediated
-‐ characteristics of carrier-‐mediated transport: 1. Saturation o based on the concept that carrier proteins have a
limited number of binding sites for the solute
o ex: glucose transport in the proximal tubule of kidney 2. Stereospecific o binding sites for solute on the transport proteins are
stereospecific o can distinguish between isomers o in contrast, simple diffusion, does not distinguish
between isomers 3. Competition o can recognize, bind, and transport chemically related
solutes o ex: D-‐glucose vs D-‐galactose (competitive inhibitor of
D-‐glucose) Facilitated Diffusion: -‐ characteristics:
o occurs down an electrochemical gradient (downhill), similar to simple diffusion
o no input of metabolic energy, therefore is passive
o at low solute concentration " more rapid than simple
diffusion o at high solute concentration " carriers can become
saturated and facilitated diffusion will level off (the rate of diffusion approaches a maximum, Vmax. It cannot rise greater than Vmax level)
o is carrier-‐mediated, therefore, exhibits stereospecificity, saturation and competition
-‐ example: GLUT 4 transporter o responsible for the insulin-‐mediated transport of D-‐
glucose from the bloodstream to the skeletal muscles and adipose tissue
o competitive inhibitors: D-‐galactose, 3-‐O-‐methyl glucose, phlorizin
o L-‐glucose (non-‐physiologic stereoisomer) is NOT recognized by GLUT-‐4
Primary Active transport: -‐ moved against an electrochemical potential gradient (uphill)
" solute is moved from an area of low concentration to an area of high contentration
-‐ there is input of metabolic energy in the form of ATP -‐ when directly coupled to the transport process " primary
active transport -‐ examples:
SAN BEDA COLLEGE OF MEDICINE Cellular Transport and Signaling BY Julianne Lopez, MD-MBA
SAN BEDA COLLEGE OF MEDICINE Page 4 of 6 Female Reproductive Physiology BY Julianne Lopez, MD-MBA
__________________________________ o main function: maintaining concentration gradients for
Na and K across cell membranes (goal: low intracellular Na and high intracellular K)
o present in the membranes of ALL cells o 3 Na+ out (ICF " ECF) & 2 K+ in (ECF " ICF) o because of this stoichiometry, more positive charge is
pumped out of the cell than is pumped into the cell (making ICF more negative) ! sub-‐units:
• alpha sub-‐units o contains ATPase activity and binding
sites of transported ions • beta-‐sub units
o has 2 states: ! E1 state: binding site for Na and K face the ICF;
enzyme has high affinity for Na ! E2 state: binding site for Na and K face the ECF;
enzyme has high affinity for K ! The cycling between the 2 states is powered by
ATP hydrolysis
check p. 9 for words ★ Clinical correlation: _________________________________ (i.e. ouabain / digitalis) are a class of drugs that inhibits Na+-‐K+ ATPase by binding to the E2 ~ P form near the K binding site on ECF side (preventing conversion back to E1) Result: _________________ intracellular Na and _________________ intracellular K __________________________________
o Main function: extrude 1 Ca2+ (for 1 ATP) from the cell (ICF " ECF) against an electrochemical gradient, which is responsible for maintaining a low intracellular Ca2+
o Present in the membrane of MOST cells o SERCA (___________________________________________________)
! Is a variant of Ca2+ ATPase found in sarcoplasmic reticulum of muscles and endoplasmic reticulum of other cells
! Function: 2 ions Ca2+ (for 1 ATP) from ICF to the interior of sarcoplasmic or endoplasmic reticulum
__________________________________
o Found in the _________________ of gastric mucosa ! Pumps H+ from ICF of pariental cells into the
lumen of stomach " acidifies gastric contents o Also found in the ______________________________ of renal
collecting duct
★ Clinical correlation: ___________________________________________________, an inhibitor of gastric H+–K+ ATPase can be used therapeutically to reduce the secretion of H+ in the treatment of peptic ulcer disease Secondary Active Transport -‐ transport of 2 or more solutes is coupled
o one of the solutes, usually _________________moves _________________ its electrochemical gradient, and the other solute moves _________________ its electrochemical gradient
o downhill movement of Na+ provides the energy for the uphill movement of the other solute
o indirect input of metabolic energy Physio Pearl: Inhibition of _________________ (i.e. by treatment of _________________), diminished the transport of Na+ from ICF to ECF, causing the intracellular Na+ concentration to increase " _________________ the size of the transmembrane gradient Implication: indirectly, all secondary active transport processes are diminished by inhibitors of the Na+-‐K+ ATPase because their energy source, the Na+ gradient, is diminished. -‐ 2 types of secondary active transport:
o Cotransport or symport o Countertransport, antiport or exchange
Cotransport -‐ form of secondary active transport in which all solutes are
transported in the_________________ direction across the cell membrane
-‐ examples:
__________________________________
o found in the absorbing epithelia of small intestine and
renal proximal tubule o both solutes are required for transport
__________________________________ -‐ present in the luminal membrane of epithelial cells of the
thick ascending limb of the Loop of Henle -‐ Countertransport (antiport or exchange) -‐ form of active transport in which solutes move in
_________________ direction across the cell membrane -‐ example:
__________________________________ __________________________________ Type of transport
Active or Passive
Carrier-‐Mediated
Uses metabolic energy
Dependent on Na+ gradient
Simple diffusion Passive; downhill
No No No
Facilitated diffusion
Passive; downhill
Yes No No
Primary Active Transport
Active; uphill
Yes Yes; direct No
Cotransport Secondary Active*
Yes Yes; indirect
Yes (solutes move in SAME direction as Na across cell
SAN BEDA COLLEGE OF MEDICINE Cellular Transport and Signaling BY Julianne Lopez, MD-MBA
SAN BEDA COLLEGE OF MEDICINE Page 5 of 6 Female Reproductive Physiology BY Julianne Lopez, MD-MBA
membrane) Countertransport Secondary
Active* Yes Yes;
indirect Yes (solutes move in OPPOSITE direction as Na across cell membrane)
*Na+ is transported downhill and one or more solutes are transported uphill
Osmosis -‐ The process of net movement of water through a selective
membrane caused by a concentration
Basic Concepts in Osmosis SOLUTION -‐ homogeneous mixture composed of two or more substances
o homogenous means that components and properties of the mixture are uniform throughout its entire volume
-‐ solute is the substance dissolved -‐ solvent is the substance that dissolves the solute OSMOLARITY -‐ concentration of all osmotically active particles (osmoles)
per liter of solution (osmol/L) -‐ colligative property that can be measured by freezing point
depression
OSMOLALITY -‐ concentration of all osmotically active particles (osmoles)
per kilogram of solvent (osmol/kg) -‐ determines osmotic pressure between solutions ISOSMOTIC -‐ two solutions that have the same osmolarity HYPEROSMOTIC -‐ solution with the higher osmolarity HYPOSMOTIC -‐ solution with the lower osmolarity
Osmotic Pressure -‐ The exact amount of pressure required to stop osmosis -‐ pressure which needs to be applied to a solution to prevent
the inward flow of water across a semipermeable membrane -‐ calculated using van’t Hoff’s law or Morse law physiologic implications: -‐ osmotic pressure is HIGHER with higher osmolality -‐ osmotic pressure is HIGHER with higher temperature -‐ the higher the osmotic pressure of a solution, the greater the
tendency for water to flow into the solution TONICITY -‐ measure of the osmotic pressure of two solutions separated
by a semipermeable membrane -‐ influenced only by solutes that cannot cross the membrane
Cell Communication and Signaling Signaling Pathways
! multiple, hierarchical steps ! amplification of the hormone-‐receptor binding event ! activation of multiple pathways and regulation of
multiple cellular functions ! antagonism by constitutive and regulated feedback
mechanisms, Signaling Molecules
! peptides and proteins Iinsulin) ! catecholamines (epinephrine and norepinephrine) ! steroid hormones (aldosterone, estrogen) ! iodothyronines ! eicosanoids (prostaglandins, leukotrienes,
thromboxanes, and prostacyclins) ! small molecules
– amino acids, nucleotides, ions (e.g., Ca++), and gases, such as nitric oxide (NO) and carbon dioxide (CO2
Mechanisms of Cellular Communication
! endocrine ! neurocrine ! paracrine ! autocrine ! juxtacrine
Endocrine Signaling ! transport of hormones along the blood stream to a
distant target organ ! EXAMPLES:
– thyroid hormone – insulin – glucagon
Neurocrine Signaling ! also called synaptic transmission ! transport of neuro-‐transmitters from a presynaptic cell
to a postsynaptic cell ! EXAMPLE:
– neuromuscular junction Paracrine Signaling
! release and diffusion of local hormones with regulatory action on neighboring target cells
! EXAMPLE: – testosterone in spermatogenesis – retinoic acid on retina
Autocrine Signaling ! a cell secretes hormones or chemical messengers that
binds to the same cell ! EXAMPLE:
– IL-‐1 on monocytes Juxtacrine Signaling
! also called contact-‐dependent signaling ! transmitted via oligosaccharide, lipid or protein
components of a cell membrane ! occurs between adjacent cells linked by gap junctions
A SOLVENT (water) undergoes osmosis from an area of low solute concentration to an area of high solute concentration. A SOLUTE undergoes diffusion from an area of high solute concentration to an area of low solute concentration.
OSMOLARITY ≠ TONICITY OSMOLARITY accounts for all solutes.
TONICITY accounts for only non-permeating solutes
SAN BEDA COLLEGE OF MEDICINE Cellular Transport and Signaling BY Julianne Lopez, MD-MBA
SAN BEDA COLLEGE OF MEDICINE Page 6 of 6 Female Reproductive Physiology BY Julianne Lopez, MD-MBA
Receptors ! Signal transducers ! Membrane receptors ! Nuclear receptors
Plasma Membrane Receptors
! Ion-‐channel linked ! G-‐protein coupled receptors ! Catalytic receptors ! Transmembrane receptors
Nuclear Receptors ! Long biological half-‐life ! Diffuse across the plasma membrane ! Bind to nuclear receptors ! hormone-‐receptor complex binds to DNA and regulates
the transcription of specific genes ! Early primary response -‐-‐" gene activation to stimulate
other genes " biological effect Signal Transduction
! Second messengers ! Involves small molecules in complicated networks
within the cell ! Signal amplification ! Molecular switches
Types of Signal Transduction Pathways ! g proteins ! ion channels ! protein kinases
– calmodulin-‐dependent protein kinases – camp-‐dependent protein kinases – anp-‐guanylyl cyclases
Ion Channel Linked Signal Transduction Pathway ! mediate direct and rapid synaptic signaling between
electrically excitable cells ! neurotransmitters bind to the receptors and either
open or close the ion channel ! Chemical "electrical signal" response ! Examples: Voltage gated-‐channels in NMJ, ryanodine
receptor, Arachidonic acid, caffeine G Protein-‐Coupled Signal Transduction Pathways
! Heterotimeric complexes -‐ α, β, and γ subunits ! are linked with more than 1000 diferent receptors ! family of integral transmembrane proteins that possess
seven transmembrane domains ! EXAMPLES:
! adrenergic receptors ! chemokine receptors ! TSH receptors
! Active ! GTP with alpha subunit ! Activation via guanine nucleotide exchange
factors (GEFs) [facilitates the dissociation of GDP and binding of GTP]
! Inactive ! GDP ! Inactivation via GTPase-‐accelerating
proteins (GAPS) and RGS proteins (regulation of G protein signaling),
! Desensitization and endocytic removal (β-‐arrestins )
! Signals ! adenylyl cyclase, phosphodiesterases, and
phospholipases Catalytic Receptors
! Many, many, many types! ! Receptor gunaylyl cyclases
– Atrial natriuretic peptide and NO ! Threonine/serine kinases
– Transforming growth factor Beta ! Tyrosine kinases
– insulin Protein Kinases
! kinase is an enzyme that modifies other proteins by phosphorylation
! phosphorylation usually results in a functional change of the target protein
– changing enzyme activity – modifying cellular location – associating with other proteins
Calmodulin-‐dependent Protein Kinases
! calcium (Ca2+) binding causes conformational alterations in calmodulin
– binds to and regulates other signaling proteins (cAMP phosphodiesterase)
– binds to calmodulin-‐dependent protein kinases
• phosphorylates specific serine and threonine residues in many proteins (myosin light-‐chain kinase)
! EXAMPLE: muscle cells cGMP-‐dependent Kinases
! binding of ANP causes dimerization and activation of guanylyl cyclase, which metabolizes GTP to cGMP
! cGMP activates cGMP-‐dependent protein kinases – phosphorylates proteins on specific serine and
threonine residues – in the kidney, ANP inhibits sodium and water
reabsorption by the collecting duct ! EXAMPLES: ANP, NO
SOURCES:
1. Guyton & Hall Textbook of Medical Physiology 12th Edition by Hall, John &, Guyton, Arthur C. , , Published in Philadelphia, Pensylvania: Saunders/Elsevier, 2011
2. Berne & Levy Physiology 6th Edition bby Berne, Robert M., 1918-‐2001., Koeppen, Bruce M., Published: Philadelphia : Mosby/Elsevier, 2008
3. BRS Physiology 5th Edition by Linda Constanzo, 2011, Published: Lippincott and Williams & Wilkins
4. Harper’s Illustrated Biochemistry 27th Edition by Murray, Robert K. by Lange
5. Basic and Clinical Pharmacology 11th Edition by by Katzung, Bertram G. , Published: New York : McGraw-‐Hill Medical, 2009
6. Various Internet Websites