Neurophysiology 3

Motor systems

Efferent output

les agents provocateurs

neurotransmitters

1.  acetylcholine (ACh)

2.  norepinephrine (NE)

3.  dopamine (D)

tyrosine and levodopa:

4.  histamine (H)

hormones

1.  epinephrine (Epi)

2.  norepinephrine (NE)

enzyme degraders

1.  cholinesterase (ACh-esterase)

2.  monamine oxidase (MAO)

3.  catechol-O-methyltransferase (COMT)

receptors

[ a quick overview of G-proteins ]

1.  M1/M3 muscarinic

ligand:  ACh

Gq activates phospholipase C

release of IP3 and DAG

increased Ca²⁺

M1:  CNS, ganglia, parietal cell secretion

M3:  contraction of smooth muscle/exocrine gland secretion

2.  M2 muscarinic

ligand:  ACh

dissociation of inhibitory Gi

inhibition of adenylyl cyclase

mediates closing of Ca²⁺ channels

slows heart rate

atropine is an antagonist

—  M4 muscarinic

activation of inhibitory Gi

found in CNS

neostriatum:  caudate nucleus & putamen

—  M5 muscarinic

coupled to Gq

release of IP3

found in CNS

substantia nigra

3.  N1 nicotinic ligand-gated ion channel (Nn)

ligand:  ACh

subunits:  α3,α5,α7,β2,β4

rapid opening of Na⁺ channel

depolarization of ganglia cells

trimethaphan is an antagonist

4.  N2 nicotinic ligand-gated ion channel (Nm)

ligand:  ACh

subunits:  α1,β1,δ,γ(ε)

rapid opening of Na⁺ channel

depolarization of skeletal muscle

tubocurarine is an antagonist

—  nicotinic ligand-gated ion channels in the CNS

—  dihydro-β-erythroidine is an antagonist

subunits:  α3,α4,β2,β4

most common

—  α-bungarotoxin is an antagonist

subunits:  α7,α8,α9

5.  alpha1 (α₁) adrenergic

ligand:  NE or Epi

Gq activates phospholipase C or A2

release of IP3 and DAG

increased Ca²⁺

contraction of smooth muscle

6.  alpha2 (α₂) adrenergic

ligand:  NE or Epi

dissociation of inhibitory Gi

inhibition of adenylyl cyclase

decrease activity

function in some presynaptic terminals & pancreatic islets

7.  beta1 (β₁) adrenergic

ligand:  NE or Epi

activation of stimulatory Gs

activation of adenylyl cyclase

increased cardiac activity

8.  beta2 (β₂) adrenergic

ligand:  Epi (NE much less so)

activation of stimulatory Gs

activation of adenylyl cyclase

relaxation or dilation of smooth muscle

—  beta3 (β₃) adrenergic

ligand:  Epi or NE

activation of stimulatory Gs

activation of adenylyl cyclase

promotes lipolysis in adipocytes

9.  D1 dopaminergic (DRD1)

ligand:  dopamine

activation of stimulatory Gs

activation of adenylyl cyclase with subsequent increase in cAMP ⇒ excitatory

vasodilatation in kidney

—  D2 dopaminergic

inhibits adenylyl cyclase, thus reduces cAMP ⇒ inibitory

↑ in schizophrenia & Tardive dysphrenia

two subtypes

—  D3 dopaminergic

inhibits adenylyl cyclase, thus reduces cAMP ⇒ inibitory

receptor is expressed in phylogenetically older regions of the brain, suggesting that it plays a role in cognitive and emotional functions

—  D4 dopaminergic

inhibits adenylyl cyclase, thus reduces cAMP ⇒ inibitory

associations have been reported of the seven-repeat (7R) allele of this receptor with both attention-deficit/hyperactivity disorder and the personality trait of novelty seeking

numerous subtypes

selective D4 agonist for Parkinsonism with fewer side effects

—  D5 dopaminergic (DRD5; DRD1B)

activation of stimulatory Gs

activation of adenylyl cyclase with subsequent increase in cAMP ⇒ excitatory

receptor is expressed in neurons in the limbic regions of the brain

10.  histamine

H1:  linked to G_q with stimulation of phospholipase C activity and the phosphatidylinositol (PIP2) signaling pathway, and the subsequent contraction of smooth muscle (bronchiolar). In the cerebral cortex, activation of H1 receptors leads to inhibition of cell membrane potassium channels.

H2:  linked to G_s with stimulation of adenylyl cyclase activity, and in the stomach leads to release of acid into the lumen. It also increases the intracellular Ca²⁺ concentrations and release of Ca²⁺ from intracellular stores.

H3:  linked to G_i with decrease in adenylyl cyclase activity. The the β and γ subunits interact with N-type voltage gated calcium channels to reduce action potential mediated influx of calcium and hence reduce neurotransmitter release.The signal transduction pattern remains to be identified; it functions, however, to reduce the release of many neurotransmitters, including histamine itself (where it acts as an autoreceptor).

H4:  linked to G_i with decrease in adenylyl cyclase activity. It is highly expressed in bone marrow and white blood cells (particularly eosinophils) and regulates zymosan-induced neutrophil release from bone marrow.
It also appears to mediate mast cell chemotaxis.

[ overview of signal transduction pathways ]
[ G-protein signaling pathways ]
[ G-protein signaling animation ]

Autonomic vs. somatic motor systems

Autonomic nervous system

two-neuron motor chain

CNS
  preganglionic fibers

ganglion
  postganglionic fibers

effector

sympathetic

functions

so-called “fight–or–flight” system

involves the E activities

excercise

blood flow to organs is ↓

blood flow to muscles is ↑

excitement

emergency

heart rate ↑

breathing is deepened and rate ↑

skin is cold and sweaty

pupils dilate

embarrassment

blood flow to facial vessels is ↑

general design

outflow is from spinal nn T₁ – L₂

sympathetic chain ganglia

collateral ganglia

adrenergic receptors

alpha (α)

excitatory response in effector organ

beta

β₁

excitatory

β₂

inhibitory

parasympathetic

functions

the “relaxed” system

involves the D activities

digestion

blood flow to organs is ↑

heart rate and blood pressure are ↓

repiratory rates are ↓

skin is warm

pupils are constricted

defecation

diuresis

general design

outflow is from cranial nerves (III, VII, IX, and X) and sacral spinal nerves (S₂ – S₄)

terminal ganglia

enteric nervous system

cholinergic receptors

nicotinic

autonomic ganglia

muscarinic

effector cells

atropine is selective muscarinic blocker

release of neurotransmitter by varicosities

dual innervation of most visceral organs

sympathetic and parasympathetic tone

sympathetic and parasympathetic dominance

control levels of autonomic activities

spinal reflexes

urination, defecation, erection

medulla

cardiovascular, respiratory, digestive centers

hypothalamus

integration of autonomic, somatic, endocrine responses

frontal cortex

emotional autonomic responses

Somatic nervous system

motor neurons act as final common pathway

end plate potential (EPP) is larger than EPSP, thus resulting in action potential

acetylcholinesterase

short duration of ACh binding:  ~10^–9 sec

vulnerabilities of the NMJ

black widow spider venom

Latrodectus hesperus

causes explosive release of ACh

botulinum toxin

molecular structure of BT

blocks release of ACh (~10^–4 mg is lethal)

curare

Chondrodendron tomentosum

competitively binds with ACh receptor

organophosphates

molecular structure of tabun (GA)

irreversibly inhibit AChE

Go to beginning

Go to beginning

Links

• Referenced sites
  
  
• Other sites
  
  
  • A short history of the development of nerve gases
    
    

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