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Neuromodulation
Modulation of synapses by amines
and peptides
Aims
 Review main cellular action of neuromodulators
 actions
through G-coupled receptors
 role of NO
 Describe the basic neural circuits for repetitive
action
 Describe effects of neuromodulation on neural
systems
 simple
behaviour: molluscan swimming and
feeding
 complex behaviour: insect ecdysis
Neuromodulators
 Amines and peptide
 5-HT,
dopamine, Adrenaline, acetylcholine…
 Oxytocin, vasopressin, CCAP
 Steroids
 ecdysone,
oestrogen
 Eicosanoids
 leukotrienes,
 NO
prostaglandins
NO
 Nitric oxide - a gas!
 synthesised from L-arginine by NOS
 neurons
(nNOS, epithelium eNOS)
 depends on Ca concentration
COO-
COO-
COO-
+ O2
C
H
NADPH
(CH2)3
C
NH2+
H2N
Arginine
+H3N C
H
+H3N C
(CH2)3
NOS
NH
NAD+
C
(CH2)3
NOS
NH
NH
+
N OH
H
H2N
N-w-Hydroxyarginine
H
C
O
NH2
Citrulline
+ NO
NO signalling
 NO diffuses freely though cell membranes
 but
not very far!
 half
life from 3-5s
 soluble guanylyl cyclase activated by NO
 elevates
cGMP
 relaxes
smooth muscle in blood vessels via PKG
and an effect on IK(Ca)
 important for heart-disease
 nitrate
(nitroglycerin) used to reduce angina
NO → cGMP
cGMP → relaxation
K channels
[Ca]
cGMP normally broken down by phosphodiesterase type 5
Viagra
 Sildenafil - best selling drug
 termtadalafil [Cialis], vardenafil [Levitra]
Viagra
 selective for phosphodiesterase - type 5 [of 11]
 so
maintains level of cGMP
 type 6 PDE,
 only
in photoreceptors,
 gives “blue flash”
 affects penile, vaginal, clitoral smooth muscle
Multi hormone control
vasoactive
intestinal
polypeptide
P2Y
receptors
for ATP
vaginal epithelial
cell
vaginal smooth muscle
Summary
 NO – local transmission as gas; no vesicles
Modulation of single cells
 Single cells can be rhythmic
 R15
in Aplysia
 sino-atrial node of vertebrate heart
 Purkinje fibres of heart
vertebrate heart
 single cell rhythm
Rhythm at sinoatrial node
Modulation of heart rate by If
 If – hyperpolarization
activated Na+ current
ACh slows rhythm
 Adrenaline accelerates

activation curve:
100% of If channels
open here
iso = isoproterenol = isoprenaline
ivabradine
 new heart drug
 blocks If
 (note
ACh)
difference from
 safer than b-blockers
Summary
 NO – local transmission as gas; no vesicles
 heart: single cell rhythm
 modulated
in different ways to give same effect
Neural circuits
 central pattern generation
 role of reflexes (see 404)
Clione
 Clione - a free
swimming sea
mollusc
 swimming
rhythm
 alternation of up and
down stroke of wings
Clione - ii
 reciprocal inhibition

7
8
7
8
up (8) / down (7)
 post inhibitory rebound
7
8
Faster with 5-HT
 CPB1 is serotonergic
heart
down
interneuron
Half centre model
 Brown (1914)
 evidence from tadpoles
I
then E due to mixed synapse
 probably at basis of most vertebrate
locomotory systems
Molluscan feeding
 Serotonin as modulator
bg
 local
neural release (CGC)
 hormonal signal in blood
 What does it target?
 How does it act?
CG
Target 1 : muscles
5-HT on voltage clamped muscle fibers
Target 2 : motoneurons
MCC is cerebral
serotonergic cell
in Aplysia; B21
is a buccal
motoneuron
Target 3: sensory neurons
sense organ in one bath
ganglion in another
Stretch evokes twitches
add 5-HT to sense organ
use low Ca to show
this effect is not due to
action on ganglion
Target 4: interneurons
control
B4 is a motoneuron
B35 an interneuron in CPG
+ 5-HT
faster
bigger EPSP
quicker decline of EPSP
Most snail effects by cAMP
Summary
 NO – local transmission as gas; no vesicles
 heart: single cell rhythm
 modulated
in different ways to give same effect
 Serotonin:
 Action
on all points of network
 Coordinated effect
 some
 Similar
cells inhibited
data exist for dopamine, octopamine,
myomodulin, FMRFamide…
Insect ecdysis
 Hard exoskeleton must be
shed periodically
 Fundamental to growth
and development
20-hydroxy-ecdysone
 juvenile hormone

 Manduca sexta

ligature, extirpation,
transplantation, injection,
Fly life cycle
larva (3 instars)
egg
pupa
adult
Drosophila
 gene knockout
 tissue/cell selective gene expression
Moulting
 weakening of old cuticle
 formation of new cuticle
 emergence
 separation
of old /new by air bubble (pre-
ecdysis)
 peristaltic waves to move forward out of old
cuticle (ecdysis)
 expansion : compression, intake of air (postecdysis)
Main peptide hormones
 ETH
 EH
 FMRFamide
 CCAP
 Bursicon
Ecdysis triggering hormone
 ETH
 26 aa peptide in Manduca
 2 peptides in flies
 secreted by Inka cells
 in response to drop
in ecdysone
ETH targets
Eclosion hormone (EH)
 In Manduca, EH released from 2 cells in brain
in response to ETH
 positive
feedback to Inka cells (which release
more ETH …)
 In Drosophila, EH thought to play lesser role;
 ecdysis
delayed by 4 min
 similar role may be played by corazonin
FMRFamide
 4 aa peptide
 secreted from Tv
neurons
 first cells to be
activated by ETH
 strengthen muscle
contractions
 Tv-KO is not lethal
CCAP
 CCAP from 5 pairs of SOG cells and 2
pairs/segment in abdomen
 In Manduca, CCAP turns off pre-ecdysis and
starts ecdysis (abdominal waves)
 In Drosophila, CCAP-KO do not start
contractions or evert head
Bursicon
 140 aa (dimer with pBurs)
 important in tanning
 released from a subset of
CCAP-cells
Bursicon
CCAP
Sequential response to ETH
Summary
 NO – local transmission as gas; no vesicles
 heart: single cell rhythm
 modulated
in different ways to give same effect
 Serotonin:
 Coordinated
action on all points of network
 Similar data exist for dopamine, octopamine,
myomodulin, FMRFamide…
 Ecdysis: Sequential program of hormone
action