Cell

Nucleus
• Nuclear membrane
• Nucleoli – site of ribosomal formation
• DNA

Cytoplasm
• Organelles
• Golgi apparatus – processing of synthesized proteins e.g. glycosylation
• Endoplasmic reticulum
• Rough ER – protein and lipid synthesis
• Smooth ER – involved in lipid metabolism
• Lysosomes – degradation of ingested products, organelles
• Peroxisomes – breakdown hydrogen peroxide
• Ribosomes – 60S/40S
• Mitochondria
• Centrosomes – spindle formation, signaling

Cytoskeleton
• Microtubules – involved in motion in cell
• Microfilaments – supportive framework of cell
• Intermediate filaments - supportive framework of cell

Cell membrane
• Intercellular connections
• Tight (occluding) junction
 Surround apical margins of cells
 Tie cells together
 Prevent movement of ions, solutes across epithelium
 Site of attachment of intracellular microfilaments
• Anchoring junctions
• Actin filament attachment sites
• Cell-cell adherens junctions ( adhesion belts)
• Cell-matrix adherens junctions (focal contacts)
• Septate junctions ( inverts only)
• Intermediate filament attachment sites
• Cell-cell (desmosomes)
 Join adjacent cells together
 Anchoring points for intermediate filaments
• Cell-matrix (hemidesmosomes)
 Attaches cells to basal lamina
• Communication junctions
• Gap junctions
 Permit passage of water, small molecules and ions from one cell
to another without crossing the ECF
 Diameter affected by Ca++, pH, voltage
• Chemical synapses
 Allow rapid passage of electrical impulses, chemical messages
• Cilia
 Move fluid, mucous or cells over the cell surface
• Cell adhesion molecules
Protein synthesis
DNA
• Adenosine-Thymine, Cytosine-Guanine
Transcription
• DNA → RNA
Post-transcription processing
Translation
• RNA → protein
Post-translation modification

Types of RNA
• Messenger RNA (mRNA)
 This will later be translated into a polypeptide.
• Ribosomal RNA (rRNA)
 This will be used in the building of ribosomes: machinery for synthesizing proteins
by translating mRNA.
• Transfer RNA (tRNA)
 RNA molecules that carry amino acids to the growing polypeptide
Mechanism of action of antibiotics
Aminoglycosides
→ misreading of genetic code

Chloramphenicol
→ prevent association of ribosomes with mRNA

Tetracycline
→ inhibit tRNA binding to ribsomes

Cellular transport
Factors:
• Molecular weight/size
• Polarity
• Charge
• Lipid solubility

Concentrations in ICF & ECF

ICF ECF E
Na+ 15 150 +60
K+ 15 5 -90
Cl- 10 120 -70

Substance cross cell membranes by:

• Simple diffusion
• Via lipid
• Down the conc. gradient
• “Unassisted” ie no enegry from the cell’s store
• E.g. O2, CO2, CO, nicotine, heroin, anesthetics, (Osmosis)

Diffusion is a process by which a gas or solute in solution expands because of the

motion of its particles to fill all the available volume

Osmosis
• Is the diffusion of a solvent through a semipermeable membrane from a
region of low solute concentration to a region of high solute concentration.
• The semipermeable membrane is permeable to the solvent, but not to the
 solute, resulting in a chemical potential difference across the membrane
which drives the diffusion
• Osmotic pressure = nRT
V

n is the no. of particles

R is the gas constant
T is the temperature
V is the volume

Solvent drag occurs when the net movement of solvent (bulk flow) drags along the
solute

• Facilitated diffusion
• Via proteins
• Down the conc. gradient
• “Unassisted” ie no enegry from the cell’s store

• Channel proteins
• Ion channels e.g. Ca++, K+, Cl-
• Gated
• Voltage
• Ligand
• Intracellular – Ca++, cAMP, G-protein
• Extracellular
• Hormones
• Neurotransmitters
• Stretch
• Non-gated

• Porins
 Small molecules up to 600 Da
• Aquaporins
 Water molecules in great quantity e.g. kidney, rbc

• Active Transport
• Via protein “pumps”
• Up the conc. gradient
• Energy required (directly from ATP or indirectly via electrochemical gradient
• Endergonic; thermodynamically unfavorable
• Enables a cell to maintain a constant intracellular non-equilibrium concentration
of specific ions etc

• Direct
• Transport coupled directly to exergonic reaction, ATP hydrolysis
• Three types of transporters
• P-type ATPases “phophorylation”
• Na-K ATPase
• H-K ATPase
• Gastric
• Renal
• V-type ATPases “vesicle”
 Pump protons into organelles of EMS
 • F-type ATPases (Factor)
 Proton transport, produces proton gradient

• Indirect

Carrier proteins transport

• Uniport e.g. rbc glucose transporter
• Cotransport
• Symport e.g. Na-glucose transporter in intestinal epithelium
• Antiport e.g. Na-K ATPase

Ion channels
• Na+
 Tetrameric
• K+
 Tetrameric
 Transient
 Voltage gated
 Inward rectification
• Cl -

 Tetrameric
• Ca++
 Tetrameric
 2nd messenger
 IP3 (Inositol triphosphate)
 DAG (Diacylglycerol)

• V ATPase (‘vesicle’)
• Organelles
• F ATPase (‘factor’)
• Oxidative phosphorylation
• Ca ATPase
Secretion of hydrochloric acid by parietal cells
• K+ moves in and out
• HCO3- reabsorbed with Cl- secretion

Na K ATPase pump
• Consists of alpha and beta subunits
• Contains ATP binding site
• Mg++ dependent
• Consumes 33% of body’s energy
• Functions:
• Maintains [Na+], [K+], RMP
• Indirectly controls [Ca++] in heart
• Enables Na+ reabsorption in kidneys
• Secondary transport of glucose, amino acids
Na+ Ca++ exchanger
• Responsible for ↑ contractility with digoxin
• Abnormalities may → diastolic dysfunction

Communication between cells occurs via:

• Synapses
• Gap junctions
• Chemical signaling
• Endocrine
 A chemical released by a specialized group of cells into the circulation and
acting on a distant target tissue
• Paracrine
 Chemical communication between neighboring cells within a tissue or organ
• Autocrine
 Chemical acts on the same cell
• Intracrine
 Signal is generated by a chemical acting within the same cell

Transport of substances across a capillary depends on:

• Pressure difference
• Area
• Permeability

Calculated osmolality

= 2[Na+] + [glucose] + [BUN] (all in mmol.l-1)

or
= 2[Na+] + 0.055[glucose] + 0.36[BUN] (glucose and BUN in mg.dl-1)
or
= 2[Na+] + [glucose] + [BUN] (glucose and BUN in mg.dl-1)
18 2.8

Osmolar gap = Measured – calculated osmolality (N = 10 mmol.l-1)

Osmolar gap ↑ with mannitol, ethanol, ethylene glycol, methanol, DKA

Tonicity is the osmotic pressure relative to plasma

Oncotic pressure is the osmotic pressure in the plasma (colloid osmotic pressure) due to the
plasma colloids (≈ 19 to 25mmHg)

Gibbs-Donnan effect
• When there is an ion on one side of the membrane that cannot diffuse through the
membrane, the distribution of the ions to which the membrane is permeable is
affected in a predictable way
• The Gibbs-Donnan effect alters the distribution of diffusable cations and anions
across any membrane where there is a non-diffusable charged species present on
one side of the membrane.
• If charged nondiffusable species are present on both sides of the membrane then two
Gibbs-Donnan effects are exerted across the membrane. This ‘double Donnan effect’
is important in stabilisation of cell volume.
• Proteins are generally large and non-diffusible (non-permeant) across membranes
and they are mostly charged (usually net negative charge).
• Gibbs-Donnan effects are widespread throughout the body in particular across the
capillary membrane & across the cell membrane.
• Product of ions on one side = product of ions on other side

Principle of the Gibbs-Donnan Effect

Solution 1 Solution 2
Na+ Na+
Cl- Cl-
Pr-
Semi-permeable membrane

Conditions:
• Two solutions (1 & 2) separated by a semipermeable membrane
• Na+ and Cl- are diffusible anions.
• Pr- represents a charged non-diffusible anion located on one side of the
semipermeable membrane (in Solution 1)

At equilibrium:

[Na+]1 x [Cl-]1 = [Na+]2 x [Cl-]2

Note: This equilibrium condition applies only if the volumes of solutions 1 & 2 are
fixed. The osmolalities are different on both sides of the membrane so there will be a
continuing osmotic force across the membrane so the situation cannot be stable if this
requirement is not met.

Plasma proteins are non-diffusable anions across the capillary membrane so a Gibbs-
Donnan effect must be present.
This will affect the [Na+] on the two sides of the capillary membrane.
 The prediction is that the [Na+] of plasma should be higher than the [Na+] of
interstitial fluid by about 6-7mmol/l but measured [Na+] in plasma and interstitial fluid
are approximately the same.
The explanation involves the ‘plasma solids effect’.

Plasma consists of 7% plasma solids (mostly protein) and 93% water. Sodium is
present only in the plasma water component. The sodium in plasma water is
effectively diluted by the proteins when measured as the [Na+] in all of the plasma.
The net effect is that even though [Na+] of plasma water is higher than [Na+] of ISF
(because of the Gibbs-Donnan effect), the measured plasma [Na+] is approximately
equal to the [Na+] of ISF. This ‘plasma solids effect’ approximately balances the
Gibbs-Donnan effect in magnitude if measurements of [Na+] are made on whole
plasma rather than on plasma water.

• Gibbs-Doonan effect →
• Osmotic pressure in ICF>ISF. This would be expected to result in movement of water
from ISF to ICF → cell swelling. In reality this is countered by the Na-K ATPase pump.
• Osmotic pressure in plasma>ISF. This leads to movement of water from
ISF→plasma.
• Different ion concentration in ICF and ISF → RMP.

Nernst equation
Calculates the Nernst potential which is the potential difference (potential inside the cell with
respect to outside the cell) that exists at 37 deg C when the electrochemical gradient is at
equilibrium.

Em is the Nernst potential

R is the universal gas constant (8.314 J mol-1 K-1)
o
T is the absolute temperature in K (273 + temp in C)
F is the Faraday constant (9.684 x 104 C mol-1)
Z is the valence of the ion (e.g. ZNa = 1)

Goldman Hodgkin? Katz? Constant field equation

• In the presence of several different ions, the equilibrium of the cell depends on the
relative permeability of the ions.
• For this, an important modification of the Nernst equation is used for calculating the
membrane potential, or more importantly for determining the PNa : PK (Permeability
ratio of ions Na : K).

E is the potential difference across the membrane in mV

R is the universal gas constant (8.314 J mol-1 K-1)
T is the absolute temperature in K (273 + temp in oC)
 F is the Faraday constant (9.684 x 104 C mol-1)
P is the permeability of the ions in cm.s-1

Resting membrane potential (RMP)

Produced by:
• Differential permeabilities of ions (Goldman constant field equation)
• Gibbs Donnan effect
• Na-K ATPase pump

G protein-coupled receptor activation

• Agonist binds to the receptor, which has a high affinity for agonists at rest.
• The binding of the agonist stabilizes a receptor conformation promotes receptor/ G
protein coupling and allows GTP to exchange for GDP on the G protein a subunit.
• The binding of GTP leads to the dissociation of the G protein from the receptor,
thereby lowering agonist affinity.
• The agonist then dissociates from the activated receptor.
• The G protein consists of three subunits (α, β, and γ) which also dissociate.
• The α subunit activates the appropriate second messenger system (e.g.,
phospholipase C for M1 receptors). The β and γ subunits can exert independent
actions.
• The α subunit is inactivated by the hydrolysis of GTP to form GDP by a GTPase
intrinsic to the G protein (GTPase activity may be activated by other intracellular
proteins called GTPase activating proteins [GAPs]).
• The α subunit (with GDP bound) can then recombine with the β and γ subunits. The
receptor is then in a high affinity state and ready for the binding of another agonist.

GDP ↔ GTP
GTPase
Nucleotide exchange
Receptors activated by G-proteins:
• Muscarinic
• Adrenergic
• Serotoninergic
• Dopaminergic
• Opioid
• Peptides

BIOCHEMICAL CHARACTERISTICS OF HETEROTRIMERIC G PROTEIN FAMILIES

Subfamily Receptors Effectors Second Messenger

Gs β-AR, α2-AR, 5-HT-R etc. →AC cAMP
→Ca2+ channels Ca2+ influx
→K+ channels K+ outflux

Gi Musc-R ; α2-AR, →AC ↓cAMP

Dopamine →PLA2 ↓Arachidonate release
Musc-R (M2), a2-AR →K+ channels K+ outflux

Gq Musc-R, Throm-A2-R, →PLC IP3, DAG, Ca2+

Brady-R, Ang-R, His-R,
Vaso-R, 5-HT-R
G12 →Na+/H+ exchanger-1
b2-AR, para-H-R, PGE1-R →Na+/H+ exchanger-1 Na+/H+ exchange
a
Abbreviations are a2-AR: a2-adrenoceptor; AC: adenylyl cyclase; Ang-R: angiotensin
receptor; Brady-R: bradykinin receptor; cAMP: cyclic AMP; DAG: diacylglycerol; Dopam-R:
dopamine receptor; Golf: olfactory G protein; His-R: histamine receptor; Musc-R: muscarinic
receptor; para-H-R: parathyroid hormone receptor; PDE: phosphodiesterase; PGE1-R:
prostaglandin E1-R; PLC: phospholipase C; PLA: phospholipaseA; Rho: rhodopsin ; 5-HT-R:
serotonin receptor; Throm-A2-R: thromboxane A2 receptor; Vaso-R: vasopressin receptor.

Gq protein
• Gq activates membrane bound phospholipase C

Actions of 2nd messengers:

• DAG →
 Activates protein kinase C
→ phosphoproteins → effect e.g. hormone release, smooth muscle contraction
• IP3 → release of Ca++ from endoplasmic reticulum →
 ↑cardiac contractility
 Exocrine secretion
 Neurotransmitter release
Fate of 2nd messengers:
• DAG → phosphatidic acid → cytosine diphosphate diacylglycerol (CDP)
• IP3 → dephosphorylation → inositol
• CDP + Inositol → phosphatidyl inositol → phosphorylation → PIP2

Adenyl Cyclase
Activated by Gs protein, inhibited by Gi protein
Effects of cAMP
• Activate protein kinase A → phosphoproteins →
 ↑activity of voltage-gated ion channels in heart
 Inactivate myosin light chain kinase in smooth muscle → relaxation
 ↑lipolysis
 ↓glycogen synthesis and glycogenolysis

Fate of cAMP
• Converted to 5’AMP by phosphodiesterase enzyme (PDE)

Other effects of G proteins

• Alter permeability of ion channels
• Act on PLA2 (phospholipase A2)

Guanyl cyclase
• Extracellular form – ANP
• Intracellular form – NO
→ ↑cGMP → adenyl cyclase → ↓cAMP → ↓Intracellular Ca++
• cGMP is converted by phosphodiesterase to 5’GMP

Receptor effector linkages

• Change in RMP – Ach receptor e.g. Noradrenaline → K+ (heart)
• 2nd messenger – cAMP, IP3, DAG, G proteins, GMP → cell effects, voltage changes
• 2nd messenger – protein phosphorylation
• Insulin tyrosine kinase → phospholipase C
• Protein synthesis – steroids, thyroid hormones
Resting membrane potential generation
• Na+-K+ ATPAse creates a concentration gradient (electrogenic pump)
• Na+, K+ leak channels allow K+ efflux and Na+ influx
• Differential permeability (K+>Na+) => RMP close to K+ Nernst potential (-86mV)
• Na+-K+ pump produces final -4mV → -90mV
• Concentration of ions on both sides equal except near cell membrane
• Cl- no role in RMP, it moves passively (-90mV). It also has no role in action potential
because its permeability is unchanged
• Gibbs-Donnan effect

Action potential
 • After depolarization
 Slower fall in potential
 ↓threshold
• After hyperpolarization
 1-2mV below RMP
 40ms
• Absolute refractory period
 Up to ⅓ of repolarisation completed
• Relative refractory period
 From end of absolute refractory period till start of after hyperpolarization

Orthodromic conduction
• Impulses move in one direction only

Antidromic conduction
• Impulses move in opposite directions

Nerve fibres
• A
• α
• Proprioception, somatic motor
• Type Ia – muscle spindle, annulospiral
• Type Ib – Golgi tendon
• β
• Touch, pressure
• Type II
• γ
• Muscle spindle, motor
• δ
• Pain, cold, touch
• Type III
• B
• Preganglionic
• C
• Pain, cold, warmth
• Postganglionic sympathetic
• Unmyelinated
 • Type IV

Sensitivity to local anaesthetics

B>C>Aδ>Aβ, Aα

Effects of ion concentration

[Na+]
• Has minimal effect on RMP because of ↓permeability
• Has effect on magnitude of action potential

Ca++
Intracellular concentration 100nmol.l-1
Extracellular concentration 1.12mmol.l-1 (12 000 X greater)
Stored in ER, organelles
Release triggered by ↑intracellular Ca++
IP3, cADPR (Cyclic adenosine diphosphate ribose, a metabolite of NAD+)
2nd messenger that acts on ryanodine receptor

Entry into cell via gated Ca++ channels:

Voltage
Ligand
Stretch

Exit out of cell

Antiport
Active transport: Ca++-H+ ATPase (Ca++ exchanged for 2H+)
Na+ exchange (Ca++ and 3Na+)

HyperCa →
• ↑contractility
• Arrest in systole
• ↓muscle, neuronal excitability

HypoCa →
• ↓contractility
• ↑excitability of neurons, muscle → tetany, spasm
• Arrest in diastole

HyperK →
• RMP less negative e.g. -40mV
• ↓refractory period
• ↓action potential duration
• ↑irritability
• ↓excitability
• Arrest in diastole

HypoK →
• RMP more negative e.g. -100mV
• ↑action potential duration
• ↑refractory period
Muscle contractions → shortening of H band & I band
Skeletal muscle triad – Sarcoplasmic reticulum + cistern
 Skeletal muscle Cardiac muscle Smooth muscle
Anatomy Gross
Proteins
T system
SR
The Sarcoplasmic Heart muscle is a 1. Multi-unit
Reticulum (SR)-T tubule network of smooth
complex (Triad) / branching muscle muscle
sarcotubular system fibers connected to 2. Single unit
1. T Tubule each other by gap smooth
architecture junctions that are muscle
2. SR Architecture strung together in a
(reticulum and structure called the
terminal intercalated disk at
cisterns) the Z line.
3. SR-T tubule
junctions
(Cytoplasmic
calcium
regulation)
SR SR SR
Well developed Found at Z Randomly
Found at A-I line located
junction
Gap junction Absent Present Present
Innervation Somatic Autonomic Autonomic
RMP/mV -90 -60 -60 (unstable)
AP duration/ms 2 200 50
Contraction
Latency/ms 2 10-50 200
Duration/ms 10 (fast) 200 Can be prolonged
100 (slow)
Spontaneous AP Absent Present Present
Refractory period
Absolute ⅓ of repolarisation Midpoint of phase
Relative 1 ms III
½ of contraction
Characteristics
Initiation Change in voltage ↑Ca++ ↑Ca++
Voltage ↑Ca++ (Cannot be
Ca++ Dihydropyridine activated by
receptor* change in voltage
like skeletal
muscle)
Contraction
Treppe† Present Present Absent
Anreppe‡ Absent Present Absent
Tetanus@ Present Present Absent
Metabolism Mitochondria ++ Few mitochondria
Aerobic
Anaerobic
Energy source 60% fatty acids
High energy 30% carbohydrates
PO4
Neurohumoral Absent Present Present
control – adrenaline

* DHP presumably acts as the voltage sensor for excitation-contraction coupling and as
a calcium channel.
This protein is coupled to a Ca++ channel in the Sarcoplasmic Reticulum (SR) called
the Ryanodine receptor protein.
The Ryanodine receptor protein is the calcium release channel in the membrane of
the SR.
Changes in voltage of the t-tubule sensed by DHP interacts with the SR’s Ryanodine-
sensitive receptor protein transiently releasing calcium from the SR into the
myoplasm.

†Treppe effect
The phenomenon of gradual increase in the extent of muscular contraction following
rapid repeated stimulation; also called staircase phenomenon
Series of maximal stimuli at less than tetanic frequency → ↑strength of contraction
Occurs due to ↑Ca++ availability
‡ Anreppe‡
↑resistance/afterload → ↑contractility → ↑SV & b.p.

@Tetanus
↑frequency of contraction → new contraction occurring before old contraction ends →
fusion of contractions → smooth contour
Tropomyosin – covers binding site of actin on myosin
Troponin I – binds actin
Troponin T – binds tropomyosin
Troponin C – binds Ca++

Excitation-contraction coupling
Nerve impulse
↓
End plate potential
↑Na conductance
AP on sarcolemma
↓
Interval spread of current to T tubule, SR
↓
↑Ca++ in sarcoplasm (↑by sustained depolarization e.g. suxamethonium)
Ca++ binds troponin C (removes inhibition of actin & myosin binding)
↓
*ATPase cleave ATP
↓
ADP on myosin
↓
Power stroke
↓
Repeat *
↓
Contraction
↓
↑pumping of Ca++ into SR, ECF, mitochondria
(↓by halothane)
(Ca++-Mg++ ATPase)
↓
↓intracellular Ca++
↓
Relaxation

Mg++ inhibits formation of X-bridges

Types of skeletal muscle

Mitochon Myosin Ca++ Diameter Myoglobi Capillary
dria ATPase pump n
(oxidative
capacity)
Type I Slow +++ ↓ Moderate Small ++ Red ++
oxidative

Type IIa Fast ++ ↑ ↑ Large ++ Red ++

(rare) oxidative

Type IIb Fast + ↑ ↑ Large + White -

glycolysis

Energy source of muscles

ATP
Phosphorylcreatine
Glycogen
Glucose
Free fatty acids
Synthesis of Ach:
+ choline
Acetate → Acetyl CoA ———————————→ Ach
Choline acetyltransferase

Metabolism of Ach:
Ach receptor
Muscle
5 subunits:
2α – binds ACh
1β
1γ
1δ

Neuronal
5 subunits
2α
3β
 Location 2nd Messenger Important effects Antagonists
M1 Brain, stomach PLC Acid secretion Pirenzipine
Pain
M2 Heart, CNS ↓cAMP Bradycardia
M3 CNS, gland +PI Secretion
M4 CNS, heart ↓cAMP
M5 CNS +PI

Noradrenaline

Tyrosine
|
Tyrosine OHlase
↓
DOPA
|
Dihydroxy phenylalanine decarboxylase
↓
Dopamine

|
OHlase
↓
Noradrenaline

|
Phenylethanolamine methyl transferase
↓
Adrenaline
Metabolism

COMT – catecholamine-O-methyl transferase, found in synaptic cleft

MAO – monoamine oxidase, found in mitochondria of nerve terminal
MAOI – monoamine oxidase inhibitor
DOMA – 3,4 dihydroxymandelic acid
Dopamine receptors:
D1 - ↑cAMP
D2 ]
D3 ] - ↓cAMP
D4 ]
D5 - ↑cAMP

Serotonin
5-hydroxy tryptamine (5HT)

Tryptophan
|
Hydroxylase
↓
5 Hydroxy tryptophan
|
Decarboxylase
↓
5 Hydroxy tryptamine
|
Aldehyde dehyrogenase/MAO
↓
5 Hydroxy Indole Acetic Acid
Actions:
↑GI motility
Smooth muscle contraction
Vascular constriction/dilatation
Platelet aggregation
Peripheral nerve stimulation
Excitation/inhibition of CNS neurons

Peristalsis
Vomitting
Platelet aggregation
Haemostasis
Inflammatory mediator
Sensitisation of nociceptors

Apetite, sleep, mood

Hallucinations
 Stereotyped behaviour
Pain perception, vomiting

Migraine, carcinoid, mood disorders

Metabolism of the catecholamine neurotransmitters. Only clinically important enzymes are

included in this diagram. The catabolic byproducts of the catecholamines, whose levels in the
cerebrospinal fluid are indicative of defects in catabolism, are underlined. Abbreviations: TH =
tyrosine hydroxylase, DHPR = dihydropteridine reductase, H2B = dihydrobiopterin, H4B =
tetrahyrobiopterin, MAO = monoamine oxidase, COMT = catecholamine-O-methyltransferase,
MHPG = 3-methoxy-4-hydroxyphenylglycol, DOPAC = dihydroxyphenylacetic acid.

Histamine

Histidine
|
histidine decarboxylase
↓
Histamine
| |
histaminidase histamine N-methyl transferase
↓ |
Imidazole acetic acid Methyl histamine
|
MAO
↓
Methyl Imidazole Acetic Acid
Glutamate
Acts on:

1. Metabutropic glutamate receptor (mGluR)

2nd messengers: PLC, cAMP

2. Inotropic receptor
• Kainate (KA)
 • NMDA
Activation leads to Ca++ entry
Blocked by Mg++ & ketamine
Activation → Long-term potentiation (LTP)
Long lasting enhancement of synaptic transmission
• AMPA
α amino
3 hydroxy
5 methyl
4 isoxazole propionate

Simple ion channel for Na+ and K+

Important for:
Pain
General anaesthesia
Neuroprotective agents

GABA
γ-aminobutyrate

Table 1. Characteristics of GABA Receptors

GABAA GABAB GABAC

G-protein coupled receptor
2nd messengers include Ligand-gated
Category Ligand-gated chloride channel
IP3, DAG → ↑Ca++, Channel
↑K+ conductance
α, β, γ, δ, ε, π
Subunits GBR1, GBR2 ρ
(GABA acts on β subunit)
Agonists Baclofen
Antagonists Phaclofen
Benzodiazepines
acts on α subunit
facilitates action
Modulator Barbiturates Zinc
↓dissociation of GABA
from receptor

Adenosine
S-adenosyl methionine → S-adenosyl homocysteine → adenosine + homocysteine

ATP ↔ ADP ↔ AMP ↔ adenosine

Pi Pi Pi

Adenosine → inosine → hypoxanthine → uric acid

Receptors:
Coupled to G-proteins
2 subtypes:
A1 receptor
 A2 receptor
Inhibitors:
Caffeine
Theophylline

Important roles:
Coronary blood flow
Renal
Immune system
CNS depression

Receptor characteristics
Post-tetanic potentiation (PTP)
Brief tetanizing presynaptic stimulation → enhanced excitatory post-synaptic potential
Due to ↑Ca++ in presynaptic membrane → overwhelm binding sites

Habituation
Repeated presynaptic benign stimulation → disappearance of response
Due to ↓Ca++ → ↓neurotransmitter release

Sensitization
Short term memory – due to ↑cAMP
Long term memory – due to ↑protein synthesis, growth of presynaptic/postsynaptic
neurons

Augmented/prolonged postsynaptic response (e.g. to noxious stimuli)

Long term potentiation (LTP)

Rapid, persistent ↑synaptic transmission
Due to presynaptic activation
Like post-tetanic potentiation but more prolonged

Serotonin

More than 14 different receptors

7 distinct families

Receptor 5-HT1 5-HT2 5-HT3 5-HT4 5-HT5 5-HT6 5-HT7

5-HT1A,
5-HT1B, 5-HT2A,
5-HT5A,
Subfamily 5-HT1D, 5-HT2B, - - - -
5-HT5B
5-HT1E, 5-HT2C
5-HT1F
ion
Effector Gi/o Gq/11 Gs ? Gs Gs
channel
2nd messenger ↓cAMP ↑IP3 ↑cAMP ?cAMP ↑cAMP ↑cAMP
8-OH-DPAT
(5-HT1A), α-methyl- 2-methyl-
Agonists - - - -
sumatriptan 5-HT 5-HT
(5-HT1B/D)
Ketanserin
Antgonists odansetron - - - -
(5-HT2A)
Only one of the 5-HT receptors is a ligand-gated ion channel; the other six belong to the G
protein-coupled receptor family.

Dopaminergic receptors

Subtypes D1 D2
Physiological Aspects of motor function Aspects of motor function & behaviour
functions (brain) (brain)
Cardiovascular function Control of prolactin & γ MSH secretion from
pituitary
Cardiovascular function
Biochemical ↑adenyl cyclase ↓adenyl cyclase
responses ↑phospholipase C ↑K+ channel
↓Ca++ channel
Localisation Caudate nucleus Caudate nucleus
Putamen Putamen
Nucleus accumbens Nucleus accumbens
Olfactory tubercle Olfactory tubercle
Cerebral cortex (brain) Cerebral cortex (brain)
Cardiovascular system Anterior & neurointermediate lobes of
pituitary gland
Cardiovascular system
Functions Post-synaptic inhibition Pre & post-synaptic inhibition

‘D1-like’ ‘D2-like’
Subtypes D1 D5 D2 D3 D4

Central dopaminergic receptor

D2 more important

Nigrostriatal pathway
Substantia nigra ---------------------------------------------------------------- striatum
D1, D2
(D3 presynaptic) inhibit dopamine release

Role: motor function

Deficiency → Parkinsonism

Mesolimbic/mesocortical
Ventral tegmentum ------------------------------------------------------------------ limbic cortex
D1, D2
(D3 presynaptic) inhibit dopamine release

Role: cognition, emotion

Tubero-infundibular
Hypothalamus -------------------------------- pituitary
D2

Role: hormonal, prolactin release inhibiting hormone (PRIH)

Area postrema (chemoreceptor trigger zone; CTZ)

 D2
Role: nausea, vomiting

Peripheral dopaminergic receptor

D1 more important

Localisation Action
Cerebral vessels Vasodilatation
Coronary vessels D2:
Renal vessels Presynaptic on sympathetic nerve
Mesenteric vessels terminals
Splenic vessels Inhibit noradrenaline release
→ vasodilatation
Kidney medulla & cortex Diuresis
Glomeruli
Proximal convoluted tubule

Note: inotropic and vasoconstrictive effect of dopamine is mediated by dopamine’s actions on

adrenergic receptors.

Reuptake of NE:
Active transport
 Stereo specific
Main mechanism for termination of action
60-75% of NE released undergoes reuptake

Termination of effect occurs by:

Reuptake
Diffusion
Extraneuronal uptake

Other modulators:
Cholinergic receptors
Muscarinic inhibits release
Nicotinic stimulates release

Factors affecting sympathetic nervous system:

Drugs
MAOI
Reuptake inhibitors
Tricyclic antidepressants
Cocaine
Inhibition of vesicular storage
Reserpine
Guanethidine
Displacement by indirect sympathomimetics
Direct agonists/antagonists
Impaired noradrenaline synthesis
Depletion of noradrenaline stores at nerve endings

Monamine oxidase (MAO) Catecholamine-O-methyl

transferase (COMT)
Structure Flavin containing enzyme + Require Mg++/divalent ion
heavy metal cofactor
Site Intraneuronal (important) Cytoplasm
- mitochondria
Extraneuronal
Organs Liver, gut, kidney, brain Liver, kidneys, brain
Types MAO-A
MAO-B
Specificity Non-specific Specific for catecholamines
Acts on:
Noradrenaline
Adrenaline
5 OH tryptamine
Methylhistamine
Inhibitors MAOI Pyragallol
Tropolone derivatives
Action Noradrenaline/adrenaline Adrenaline
↓ ↓
Dihydroxy mandelic acid Metadrenaline
(DOMA)
Noradrenaline
Metadrenaline ↓
↓ Normetadrenaline
Vanillyl mandelic acid
Dihydroxy mandelic acid
(DOMA)
↓
Vanillyl mandelic acid

Calcium channels
1. Voltage sensitive types
T (transient)
L (long lasting)

2. Non-voltage gated types

N ( non T non L)
cAMP → widen gate → ↑Ca++ influx
cGMP → narrows gate → ↓Ca++ influx
3. Non-gated types
P
Q
R
Location Function Drugs affecting
T Type CNS Regulation of burst Volatiles → inhibit
PNS firing Propofol → inhibit
Muscle Repetitive discharges
Secretory cells as pacemaker in
neurons
L Type Neuronal cell bodies ?Mechanism of Ca++ antagonists →
anaesthesia inhibit (nifedipine)
N Type Nervous system Control of Volatiles → inhibit
Endocrine cells neurotransmitter Ca++ antagonists →
release inhibit (verapamil)
Opioids → inhibit
P Type CNS Mediate central Isoflurane → inhibit
Nerve terminals synaptic transmission