Neurobiology, lecture on neuromodulators/neuropeptides
USD Department of Biology
Summers
Neurobiology text:
Principles of Neural Science

- Kandel, Schwartz and Jessell:
Read pages 289-296 for this lecture
acronyms

end
XXIII. Neuromodulators and Neuropeptides  	  back to XXI. Neuroactive Steroids 

	A. Neuromodulators alter the action of transmitters

		1. enhancing or reducing transmitter effectiveness, but 
		   not directly stimulating neural transmission

			a. transmitter synthesis, release, receptor binding and
			    unbinding, reuptake and catabolism are affected by
				different neuromodulators

		2. many hormones are neuromodulators

			a. ACTH and cortisol/corticosterone stimulate
			    TH, DBH, and PNMT

				i. stress hormones stimulate the production of
				    sympathetic neurotransmitters

		3. excitatory/inhibitory amino acid transmitters
		    have neuromodulatory roles

	B.  Neuropeptides often act as neuromodulators

		1. more than 50

			a. many are hormones

		2. as transmitters/modulators peptides are released
		    close to the site of action

		3. actions in the CNS may be similar to
		    peripheral hormonal action

			a. e.g. endorphins and enkephalins are localized
			    in regions of the brain associated with pain

			b. e.g. MSH, ACTH, & b-endorphin
			     regulate complex central responses to stress

			c. e.g. GnRH and Oxy affect sexual/reproductive behavior

		4. may act as a conventional transmitter,
		    cause excitation, inhibition or both

			a. and have modulatory effects such as altering the
			    time course or magnitude of transmitter release,
			    altering receptor binding or reuptake

			b. and have combined effects to modulate
			    behavior, sensibility, and emotion

	C. Families of Neuroactive Peptides

		1. Members of each family are structurally related

			a. stretches of similar amino acid sequences

				i.\ derived from related genes

					(1) divergent or convergent evolution

					(2) phylogenetically conserved

		2. structurally related peptides may have similar functions

			a. may mediate the same or similar physiological processes

				i. may bind with limited affinity to the other's receptor

		3. Opioids

			a. enkephalins, dynorphins, endorphins

		4. Neurohypophyseal

			a. AVP, Oxy, neurophysins

		5. Tachykinins    (rapid, move)

			a. substance P, bombesin, substance K (neurokinin A)

		6. Secretins

			a. secretin,  glucagon,  VIP,  GIP,  GHRH

		7. Insulins

			a. insulin,  IGF1,  IGF2

		8. Somatostatins

			a. somatostatin,  PP (pancreatic polypeptide)

		9. Gastrins

			a. gastrin,  CCK

		10. functions within a group may be dissimilar

	D. Several Neuroactive peptides may be encoded
	    on a single continuous strand of mRNA

		1. large precursor molecule

			a. e.g. POMC = proopiomelanocortin

				i. aMSH,  ACTH,  b-endorphin

		2. no high affinity reuptake mechanism
		
		
			a. enzymatic degradation necessary for removal


		3. post-release cleavage products may provide signals

			a. catabolism does not end signal

			b. catabolite may effect pre- and post-synaptic cells

			c. fine tune interactions between peptides and other
			   coexisting transmitters

	E. Peptides and small-molecule transmitters coexist
	    in the same synapse = colocalization

		1. may be coreleased

			a. cotransmission

		2. vesicles that release peptides differ from those of
		   small-molecule transmitters

		3. examples:
transmitter peptide location
5-HT substance P raphe
TRH
enkephalin
GABA somatostatin cortex & hippocampus
NE neurotensin LC
DA CCK VTA
neurotensin

	F. example of neuropeptide as neuromodulator:
		Neurotensin (NT)
		
		1. widely expressed in CNS and periphery (small intestine)
		
		2. Synthesis: cleaved from 170 aa prohormone
		
			a. 1 exon includes NT and Neuromedin (NMn)
			
			
			b. related peptides in birds (LANT6) and frogs (xenopsin)
			
		
		3. enzymatic inactivation: metalloendopeptidases
		
		
			a. no high affinity  reuptake process (like other peptides)
			
		
		4. Internalization
		
		
			a. bound to autoreceptor
			
			
				i. retrograde transport like neurotrophins
			
			
			b. modify cell action
			
			
				i. e.g. ñ DA cell TH expression in striatum
	
	G. example 2:    CRF effects in limbic system

		1. CRF containing circuits from amygdala and hypothalamus
		    innervate extensive group of neurons in pons, medulla,
			cortex and amygdala (interneurons)

			a. stress-related circuitry

				i. hormonal: CRH (=CRF) from PVN ® ñ ACTH
				  from pituitary ® ñ B/F from adrenal
				  
				  
				ii. neuroactive: CRF from central Amygdala
				   (CeA) ® ñ GABA in CeA ® ¯ GABA in BNST
					        (bed nucleus of stria terminalis) ® ñ PVN


					(1) CeA CRF ® ñ LC ® ñ NE


					(2) CeA CRF ® ¯ raphe ® ¯ 5-HT
				

						(a) but effects of CRF on 5-HT in terminal
						    regions like hippocampus or striatum can
							be dose or exposure dependent
							
							
							(i) in striatum low dose® ¯ 5-HT
								high dose® ñ 5-HT
				
				
		2. two receptor types:CRF-R1 and CRF-R2 & 2a
		

			a. both activate Ca++ channels via Gs ®AC ... but ...

			b. CRF-R1 are excitatory
			
			
				i. potentiate Glu 
				
				
			c. CRF-R2 are inhibitory
			
			
			d. distribution determines effect
			
			
				i. relation to Glu or GABA
				
				
		3. CRF ® ñ APs of cells that fire in
		   bursts: hippocampal pyramidal cells

			a. can promote seizure-like activity of limbic system

		4. anxiogenic + stimulates spontaneous locomotion

XXIV. Synaptic Vesicles



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