Explain why neurotransmitters act sometimes via metabotropic receptors and at other times via ionotropic receptors

Sanjay Manohar (Oxford 2015)

Define neurotransmitter:
 - molecule, synthesised and released presynaptically, diffuses, specific receptor on postsynaptic surface. Broken down - so long effects must be mediated by postsynaptic cell.
 - Cajal 1890s - 30 nm gap => not electrical?
 - Otto Loewi 1921 - vagus extract slows heart -> chemical 
 - Dale's law.
 - Difficulties defining: volumetric, hormones, gases

Classification:
  Amino acids- Glu GABA Gly
  Monoamines - DA, NA, 5HT, Adr, histamine
  small molecules - ACh, NO, Adenosine
  peptides - substance P, opioids, oxytocin, orexin (many)

Key experiments to describe
	Bernard Katz 1951- mEPP
	Rodbell 1969 glucagon operates via GTP: "second messenger"
	Gilman  1970s adrenaline increases cAMP in mouse neuron cultures
	Equilibrium potentials
	Artificial membrane & fluid mosaic model
	Crystallography
	Electron microscopy
	Immunocytochemistry

Metabo vs Iono: Similarities
  transmembrane receptor protein
  ligand binding
  synaptic transmission of information

IONO                         METABO
=========================================
Physical:::

Channel opening              G protein activation
EPSP/IPSP                    Second messenger cascade
milliseconds                 seconds

Function:::
-----------
Temporal integration         Synaptic growth
Spatial integration          Receptor expression / transcription factors
Rapid responses              Amplification
Representing and computing   Neuromodulation - eg arousal, attention, mood
                               eg phosphorylation of K channels
                             Adaptation (retina) / stateful
                             presynaptic autoreceptors
Drug target for epilepsy     Drug target for cognitive effects
                           
Examples:::
-----------
NAchR - muscle contraction   Muscarinic AChR - glands, slow heart           
Glut AMPA - computation      MGluR - plasticity, memory, LTP/D
GABA-A                       GABA-B
                             Peptides, hormones, dopamine
Pyramidal neuron             Photoreceptor
Muscle                       Heart
Ear hair cell                Smell
 fine-grained timing				  extreme sensitivity
                             
Types:::
--------
Na (+)                       Gs
Ca (+)                       Gi
K  (-)                       Gq
Cl (-)
NMDA as a complex case!

Graph of EPSP                Diagram of G protein


How G proteins work
===================
Beta          -> Gs ->  adenylyl cyclase -> ATP-cAMP -> PKA
muscarinic M3 -> Gq ->  PLC  -> PIP2-IP3 -> Calcium release -> CaMK
rhodopsin     -> Gi ->  PDE  -> cGMP-GMP -> closes Na channels

Multiple upstream effects - cell and situation specific.