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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