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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
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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, prostaglandins • NO
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 +H3N C H + NADPH NAD+ +H3N C H NO (CH2)3 (CH2)3 (CH2)3 NOS NOS NH NH NH + C NH2+ C N OH C H H2N H2N O NH2 Arginine N-w-Hydroxyarginine Citrulline
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
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
Modulation of heart rate by If activation curve:100% of If channels open here • If – hyperpolarization activated Na+ current • ACh slows rhythm • Adrenaline accelerates iso = isoproterenol = isoprenaline
ivabradine • new heart drug • blocks If • (note difference from ACh) • 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
78 Clione - ii 78 • reciprocal inhibition • up (8) / down (7) • post inhibitory rebound 78
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 bg • Serotonin as modulator • 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 bathganglion in anotherStretch 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 + 5-HT fasterbigger EPSPquicker decline of EPSP B4 is a motoneuronB35 an interneuron in CPG
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 cells inhibited • Similar data exist for dopamine, octopamine, myomodulin, FMRFamide…
Hard exoskeleton must be shed periodically Fundamental to growth and development 20-hydroxy-ecdysone juvenile hormone Manduca sexta ligature, extirpation, transplantation, injection, Insect ecdysis
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 (post-ecdysis)
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 dropin ecdysone
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
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