in this presentation I explained about cell membrane structures, membrane transport, resting potential, action potential,.....

1. In the name of GOD

2. Physiology of the cell
by
H. Khorrami Ph.D.
http://khorrami1962.spaces.live.com
khorrami4@yahoo.com

3. Contents:
• Plasma membrane
• Some cellular organells
• Transport across membrane
• Membrane potential: resting & action potential
• Refractory period
• Chronaxie, rheobase, length constant,
• Synapses, electrical & chemical
• EPSP, IPSP
• Adaptation, plasticity, post tetanus potentiation, long term potentiation
• Lateral inhibition, synaptic fatigue,
• Receptive field
• Summation: temporal, spacial
• Signal transduction
• G-proteins
• Apoptosis & necrosis
• Muscle fiber, neuromuscular junction, contraction, twitch, motor unit,
• Isometric & isotonic contraction
• Muscle metabolism, fatigue

4. Cell membrane
• Two layer phospholipids ( 45% of weight)
• 2 × 1.7 + 0.1 nm
• Proteins ( 55% of weight)
• + 2 × 2nm
• Structural
• Integral
• Channel
• Pump
• Enzymes
• Receptors
• Orphan
• Non-orphan
• Carbohydrates

5. Properties of membranes

8. Fluid mosaic model

9. Lipids

10. Phospholipids

12. Membrane lipids

13. Fatty acids

14. Phospholipids' head groups

15. Fatty acid tails

16. Glycolipids

17. Cholesterol

18. Membrane asymmetry

19. Organelle lipids

20. Lateral organization

21. Membrane curvature

22. Transport of lipids

23. Lipid synthesis

24. Non-vesicular lipid transport

25. Movements in membrane
• Phlip-phlap
• Rotation
• Lateral diffusion ( 107 per second)
• Flexion

26. Functions of carbohydrates
• Negative surface charge
• Attachment of cells together
• As receptor
• Immune recognition

27. Lysosomes
Lysosomal storage
Enzyme involved Problem
disease(LSD)
Pompe α-glucosidase Glycogen in hepatocytes
MPS Glycosaminoglycans
Tay-Sachs Hexosaminidase A Gangliosid
Hypoxanthine-guanine-
Gout Uric acid
phosphoribosyl-tansferase
Leprosy, silicosis,

29. Na: 15
Na: 145
Cl: 4
Cl: 104
K: 150
K: 5
Mg
Ca: 10-3
-
PO4+
Hco3
AA
Glucose
Fat
Po2
Pco2
PH: 7.40
Protein
PH: 7.00

30. Osmosis
• Osmolarity
• Osmolality
• Isotonic, hypotonic & hypertonic

31. Osmosis

32. Osmotic pressure
• Based on decrease in freezing point
• A one molar solute -1.86⁰ C
• Plasma… -0.52
• 280mmol
• pv=nRT, p×1=1×62.63×310
• A one molar solute 19200mmHg
• Osmotic pressure of plasma?
• 5600mmHg

33. Could a hyperosmolar solution be isotonic?
• Yes
• Because tonicity depend on permeability of
the membrane

34. Membrane transport
• Diffusion
• Facilitated diffusion
• Active transport

35. Simple & facilitated diffusion
Simple diffusion Facilitated diffusion
No saturation Saturation(Vmax)
Fast Low velocity
Chemical gradient Carrier protein
Linear correlation Non-linear correlation
Competition

36. Diffusion
• Fick’s law:
• J = - DA(dc/dx)

37. Secondary active transport
• Symport
– Intestine
– Kidney
– Glucose & AA
• Antiport
– Heart
– Rbc
– Calcium, H+, HCO3, Cl- …

38. Ion Channels
• Leak channels
• Voltage-gated channels
• Ligand-gated channels
– Intracellular
– Extracellular
• Mechanically-gated channels

39. Sodium channel

42. Glucose transporters
transporter tissue function insulin stimulation
• Facilitative glucose transporters
• GT-1 BBB, Rbc, fibroblast glu uptake +
• GT-2 liver,β cell, intestine low-affinity -
• GT-3 brain, fibroblast glu uptake ?
• GT-4 fat, skl. muscle, heart glu uptake +++
• GT-5 small intestine, sperm fruc. transp. ?
• Active glucose transporters
• SGT-1 intestine, kidney intes. renal reabs -

44. Resting potential

45. Resting potential

46. Action potential

47. Na-voltage gated channel

49. Action potential

50. Threshold

51. Na channel

52. Review

53. Falling phase

54. Undershoot

55. Refractory period

56. Resting state

57. Depolarising phase

58. Repolarising phase

59. Undershoot

60. Blocking the channel

61. Potassium channels in AP
• Delayed rectifier K ch
– In repolarization
• Early K ch
– Reduce the velocity of depolarization
• Calcium-activated K ch
– Preventing repetitive stimulation

62. Action potential equations
• Nernst:
– Ek= -RT/ZF Ln [K]i/ [K]o
• Goldman-Hodgkin:
– Ek= -RT/ZF Ln P[K]i+ P[Na]i+ P[cl]o/ P[K]o+ P[Na]o+
P[cl]i

65. Comparison of synapses
Electrical Chemical
Bidirectional Unidirectional
No delay Delay (1-2ms)
Fast Slow

66. Century 21st

68. Gap junction

70. Electrical synapse

74. Gap junction

75. K channel

76. Nernst equation

77. Goldman equation

87. Functions of the electrical transmission
1.Electrical synapses are more reliable, less likely to fail.
2.Greater speed –important in rapid reflexes involving escape reactions.
3.The synchronization of electrical activity of groups of cells.
4.Intracellular transfer of molecules such as Ca, ATP and cAMP.
5.The activity of gap junctions between cells in the retina can be modulated by
dopamine. Thus the gap junctions can be dynamic components of neuronal
circuits.
6. Mutations in the genes encoding gap junction proteins cause diseases:
•Peripheral neuropathy –Charcot-Marie-Tooth disease
•Abnormal cardiac development
•Congenital deafness
Charcot-Marie-Tooth disease –inherited peripheral neuropathy
-degeneration of peripheral nerves
-Foot deformities, muscle wasting, distal sensory loss, decreased tendon
reflexes
Gap junction is necessary for radial migration in the neocortex

88. Chemical synapse

90. Chemical synapse
• neurotransmitter
• Depolarization of the presynaptic nerve
terminal
• Triggers the release of molecules Interact with
receptors on the postsynaptic neuron
• Excitation or inhibition of the postsynaptic
neuron.

91. Neurotransmitters:
Definition:
• Synthesized by presynaptic neuron
• Released by stimulation
• Microapplication of NT. Mimic the presyn. stimulation
• Presynaptic & microappl. Stim. Must be blocked by
pharmacologic agent
• High affinity uptake mechanism for the substance in
synaptic terminal
release of NT, synapsin
6/9/2010 91

92. Neurotransmitters
• Small molecules • Neuropeptides
 Opioid peptides
 Ach Leucine enkephalin
 Biogenic amines Methionine enkephaline
b - endorphin
Dopamine Dynorphins
Norepinephrine  Pituitary peptide
Epinephrine Oxytocin
5-HT Vasopressin
ACTH
Histamine
TSH
 Amino acids  Gastrointestinal peptides
Aspartate CCK
GABA Sub-P
Glutamate
Neurotensin
Glycine
Homocystein Gastrin
Taurine Insulin
 Nucleotides Glucagon
Adenosine Somatostatin
ATP  Others
 Retrograde gases Angiotensin
Nitric oxide Bradykinin
Carbon monoxide
Neuropeptide Y
6/9/2010 92

93. Receptors of NTs
• Ionotropic: • Metabotropic:
ligand gating i.e. nicotinic work by second
receptor (inhibited by messenger
curare) (G protein)
6/9/2010 93

94. Neuropharmacology of some receptors
Neurotransmitter Receptor subtype Agonist Antagonist
Acetylcholine(Ach) Nicotinic receptor Nicotine Curare
Muscarinic Muscarine Atropine
receptor
Glutamate AMPA AMPA CNQX
NMDA NMDA AP5
GABA GABAA Muscimol Bicuculine
GABAB Baclofen Phaclofen

95. Acetylcholine

96. Catecholamines

97. Serotonin synthesis

98. Glutamate receptor
• Non-NMDA; • NMDA;
• kainate receptor & • Gating channel is
• AMPA permeable to Na, K, Mg
– permeability  to Na & & Ca2+
K • Magnesium block
– Excitatory
• Act on this receptor
– Act on this receptor at
when depolarized
rest
(voltage-dependent)
N-Methyl-D-Aspartate ,
α-amino-3-OH-5-methyl-4-isoxasole propionate
6/9/2010 98

99. Glutamate receptors

100. Calcium can trigger
• Enzymatic activity
• Opening of a variety of channels
• Gene expression
• Cell death
• Long-term memory

101. Glutamate receptors
• Activation of AMPA
• Na+ inward & K+ outward
• Depolarization
• Pop out of Mg2+ from the pore of NMDA

103. Voltage-dependent NMDA

104. Excitotoxicity
• High demand of brain cells to oxygen & glucose
• Cardiac arrest, stroke, …..
• Limits of ATP
• Depolarizing the membrane
• Calcium leak into cells
• Glutamate release
• Depolarization
• More calcium
• ……………
• Cell death

106. TTX

107. Length constant

112. Components of a second messenger
cascade

117. Nicotinic receptor

118. Acetylcholine

120. Acetylcholine receptors
Name Location Blocked by Agonists
Muscarinic End of postgang. Atropine Metacholine
parasym Carbachol
Betanechol
Pilocarpine
Nicotinic Autonomic ganglia Scopolamine Nicotine
Adrenal medulla Hexamethonium
N-M junction Tubocurarine

121. Ach (muscarinic receptor)

124. Norepinephrine

125. Inhibitory neurotransmitter

131. Cell-to-cell communication by extracellular
signaling usually involves six steps
• 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
• Detection of the signal by a specific receptor protein
• A change in cellular metabolism, function, or development
triggered by the receptor-signal complex
• Removal of the signal, which usually terminates the cellular
response

132. Signaling molecules operate over various
distances in animals

133. Cell-surface receptors

135. Signal transduction steps
• Ligand binds to the receptor
• Dissociation of a subunit from b & g
• Exchanging GDP with GTP
• Moving a subunit
• Activation of adenylyl cyclase or GC
• Second messenger( cAMP)
• Binding cAMPs to R subunit of Protein kinase
• Dissociation & activation of C subunit
• Phosphorylation of target protein
• Cell response

136. Cell-surface receptors

137. Second messengers

138. Other conserved proteins function in signal
transduction: GTPase switch proteins

139. Other conserved proteins function in signal
transduction: protein kinases

140. Other conserved proteins function in signal
transduction: adapter proteins

141. Common signaling pathways are initiated by
different receptors in a class

142. hormone
signal
outside
GPCR plasma
The a subunit of membrane
a G-protein (Ga) a g g  a cytosol
binds GTP, & can AC
GDP b b GTP
hydrolyze it to
GDP + Pi. GTP GDP ATP cAMP + PPi
a & g subunits have covalently attached lipid anchors that
bind a G-protein to the plasma membrane cytosolic surface.
Adenylate Cyclase (AC) is a transmembrane protein, with
cytosolic domains forming the catalytic site.

143. hormone
signal
outside
GPCR plasma
membrane
a g g  a cytosol
AC
GDP b b GTP
GTP GDP ATP cAMP + PPi
The sequence of events by which a hormone activates
cAMP signaling:
1. Initially Ga has bound GDP, and a, b, & g subunits
are complexed together.
Gb,g, the complex of b & g subunits, inhibits Ga.

144. hormone
signal
outside
GPCR plasma
membrane
a g g  a cytosol
AC
GDP b b GTP
GTP GDP ATP cAMP + PPi
2. Hormone binding, usually to an extracellular domain
of a 7-helix receptor (GPCR), causes a conformational
change in the receptor that is transmitted to a G-protein
on the cytosolic side of the membrane.
The nucleotide-binding site on Ga becomes more accessible
to the cytosol, where [GTP] > [GDP].
Ga releases GDP & binds GTP (GDP-GTP exchange).

145. hormone
signal
outside
GPCR plasma
membrane
a g g  a cytosol
AC
GDP b b GTP
GTP GDP ATP cAMP + PPi
3. Substitution of GTP for GDP causes another
conformational change in Ga.
Ga-GTP dissociates from the inhibitory bg complex & can
now bind to and activate Adenylate Cyclase.

146. Identification and purification of cell-surface
receptors
Hormone receptors are detected by binding assays

147. KD values for cell-surface hormone receptors
approximate the concentration of circulating hormones

149. G protein-coupled receptors and their
effectors
• Many different mammalian cell-surface receptors are
coupled to a trimeric signal-transducing G protein
• Ligand binding activates the receptor, which activates the G
protein, which activates an effector enzyme to generate an
intracellular second messenger
• All G protein-coupled receptors (GPCRs) contain 7
membrane-spanning regions with their N-terminus on the
exoplasmic face and C-terminus on the cytosolic face
• GPCRs are involved in a range of signaling pathways,
including light detection, odorant detection, and detection of
certain hormones and neurotransmitters

150. G protein-coupled receptors

151. The structure of adenylyl cyclase

152. Trimeric Gs protein links b-adrenergic receptors
and adenylyl cyclase

153. Some bacterial toxins irreversibly modify G
proteins

154. Adenylyl cyclase is stimulated and inhibited by
different receptor- ligand complexes

155. Types of G-proteins
• Ras (growth factor signal cascades)
• Rab (membrane vesicle targeting and fusion)
• ARF (formation of vesicle coatomer coats)
• Ran (transport of proteins into & out of the nucleus)
• Rho (regulation of actin cytoskeleton)

157. Ras cycles between active and inactive
forms

158. Receptor tyrosine kinases and Ras
• Receptor tyrosine kinases recognize soluble or membrane
bound peptide/protein hormones that act as growth factors
• Binding of the ligand stimulates the receptor’s tyrosine
kinase activity, which subsequently stimulates a signal-
transduction cascade leading to changes in cell physiology
and/or patterns of gene expression
• RTK pathways are involved in regulation of cell proliferation
and differentiation, promotion of cell survival, and modulation
of cellular metabolism
• RTKs transmit a hormone signal to Ras, a GTPase switch
protein that passes on the signal on to downstream
components

159. Ligand binding leads to
autophosphorylation of RTKs

160. An adapter protein and GEF link most
activated RTKs to Ras

161. Opening of ryanodine receptors releases Ca2+
stores in muscle and nerve cells

165. Signal transduction