Summers

Neurobiology text: Principles of Neural Science - Kandel, Schwartz and Jessell: Read pages 280-286 for this lecture end acronyms

XXI. Amino Acid Transmitters  			back to XX. Transmitter Anatomy

	A.  Glutamate (Glu) and Aspartate (Asp) are excitatory amino acids
	    
		1. universal cellular constituents (with glycine)
		    incorporated into the proteins of all cells


		2. formed from NH2 and a-ketoglutarate (from glucose via Kreb's cycle)


			a. a-ketoglutarate transaminase


			b. catabolism reverse


			c. glutamate is the immediate substrate for GABA


		3. mediate brief, intense excitatory actions at ionotropic receptors
		
		
			a. called excitatory amino acids


			b. membrane depolarization by increased Na+ conductance


		4. Receptors


			a. AMPA (a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid) and
			   KA (kainate)   
			   

				i. Glu-gated (opens) Nai+/Cai++/Ko+ channels = ionotropic
				
				
				ii. mediate fast excitatory synaptic transmission
				
				
				iii. composed of transmembranal protein subunits:
				      GluR1, GluR2/3


			b. NMDA (N-methyl-D-aspartate)


				i. Glu-gated (opens) Cai++/Nai+/Ko+ channels


				ii.  made of 5 subunits: NR1 + NR2A-D


				iii. requires Mg++ binding in the channel


				iv. facilitated by AMPA or KA depolarization  


					(1) AMPA-R cluster near NMDA-R


					(2) ­ intracellular Na+ ® ­ NMDA channel activity


					(3) postsynaptic density proteins link receptors
					
					
						(a) PSD95, GKAP, Shank


				v. ionotropic receptor family bind multiple ligands
				
				
					(1) NMDA binds Glu, Gly, Zn++ & polyamines
					    extracellularly
					
					
					(2) Mg++ & PCP in channel
					
					
					(3) steroids near lipid bilayer
					
					
					(4) Na+ intracellularly


				vi. high densities in hippocampus and cortex


					(1) pivotal role in long-term potentiation (LTP),
					   long-term depression (LTD) and developmental plasticity
					   
					   
			c. metabotropic (mGlu-R1-7)
 				ACPD (trans-1-aminocyclopentane-1,3- dicarbyoxylate)


				i. slow synaptic responses, widespread distribution


					(1) affect synaptic transmission and synaptic placticity
					
					
						(a) D threshold Vm for action potential
					
					
				ii. pre- or post-synaptic
				
				
					(1) may be autoreceptors


				iii. mGlu-R1 & mGlu-R5 activate Gp ® PLC ® DG/IP3 ® Ca++


				iv. mGlu-R2  & mGlu-R3: Gi ®x AC ®cAMP


				v. mGlu-R4, mGlu-R6, mGlu-R7 & mGlu-R8: Gi ®x AC ®cAMP


		5. Reuptake by Na+ coupled neuronal (GTn)  and glial (GTg) transporters  


			a. both kinds of cells take up Glu to terminate signal and recycle


				i. protect cells from excitotoxic damage


			b. Glu taken up by glia converted to glutamine (Gln) then
			   transported back to the neuoron


				i. Gln synthase


				ii. mitochondiral glutaminase converts Gln ® Glu


		6. more glutamate/aspartate cells than all other cells in the NS combined


			a. 10-100 billion


			b. transmitter for the granule cells of the cerebellum


			c. also cortical input to the hippocampus, striatum, and olfactory cortex


			d. gray matter of the spinal cord


	B. g-aminobutyric acid (GABA)	      NH2-CH2-CH2-CH2-COOH


		1. formed from Glu by L-glutamic acid decarboxylase (GAD)


			a. GABA shunt: bypass from Kreb's to provide glutamate


			b. GABA catabolized by GABA-T
			(GABA transaminase = a-ketoglutarate aminotransferase)

				i. NH3 to glutamate synthesis


		2. inhibitory amino acid transmitter = inhibits firing of neurons


		3. Receptors - 2 major types  


			a. GABAA = ligand-gated Cl- channel


				i. postsynaptic inhibition:
				    hyperpolarizing postsynaptic membrane
					
					
					(1) influx of Cl-


				ii. presynaptic inhibition:
				     slightly depolarize ® reduced transmitter released
					 
					 
					(1) modulates sensory input


				iii. 5 subunits - 2a + 2b + 1g  (usually)


					(1) a binds benzodiazepines (valium)


					(2) b binds GABA
					
					
					(3) other sites near membrane bind barbiturates, anesthetics,
					    alcohols and H2O, neuroactive steroids; and
						inside bind convulsants and picrotoxin


					(4) extraordinary structural diversity: a1-6, b1-4, g1-3, d, r1-2


					(5) superfamily of ligand gated channels including
					    nicotinic, NMDA, AMPA, KA & glycine-R


			b. GABAB 	(fewer)


				i. often presynaptic
 
 
					(1)G K+ ® open K+ or close Ca++ channels


						(a) autoreceptors inhibit GABA neurons
						    by hyperpolarization

						
					(2) also Gi® X AC


				ii. sometimes postsynaptic 
				
				
					(1) ­ phospholipase A2 ® ­ cAMP 


			c. GABAC in retina
			
			
				i. more sensitive Cl- channel


			d. GABA transporter


		4. projections from the hypothalamus to cerebral cortex


			a. direct pathway for limbic, emotional, and visceral information
			    to reach the cortex


			b. projections of striatum to substantia nigra


			c. intrinsic neurons in cortex, hippocampus, cerebellum,
			   olfactory bulb and retina...


	C. glycine (Gly)


		1. an inhibitory amino acid neurotransmitter


			a. postsynaptic hyperpolarization - receptor is a Cl- channel


				i. 5 subunits: glycine and strychnine bind to a


			b. binds to NMDA receptors too


				i. prevents desensitization - excitatory


			c. GlyT1 = glial & GlyT2 = neuronal transporters


		2. Gly formed from glucose via conversion to serine


			a. or from isocitrate (Kreb's) via glyoxylate (using a-ketoglutarate transaminase)


				i. both are reversible


		3. distributed in the brainstem and spinal cord: inhibits interneurons
		   onto motor neurons

XXII. Neuromodulators and Neuropeptides

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