SAN BEDA COLLEGE OF MEDICINE Cellular Transport and Signaling BY Julianne Lopez, MD-MBA SAN BEDA COLLEGE OF MEDICINE Page 1 of 6 Cellular Transport and Signaling by Julianne Lopez, MDMBA [email protected]09178520849 Cellular Transport and Signaling EDUCATIONAL OBJECTIVES At the end of the 4hour lecture, the future Bedan Doctor must be able to: • Illustrate the fluidmosaic 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. ! GProtein 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
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
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
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
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:
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
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
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
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
! 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