Summers

Neurobiology text: Principles of Neural Science - Kandel, Schwartz and Jessell: Read pages 229-251 for this lecture end acronyms

XXVI. 2nd Messenger systems  			back to XXV. Receptors

	A. Intracytoplasmic segments of receptors are coupled to G proteins



		1. G proteins activate a cascade of enzymatic action
		   = 2nd messenger system


			a. the kind of enzymes that are activated determine the
			   action in the cell


				i. i.e. the action of the transmitter or modulator


		2. intracytoplasmic segments also may have intrinsic tyrosine
		   protein kinase activity


			a. no G protein necessary


				i. phosphorylation sites


	B. cAMP    


		1. receptor binding  catalyze GTP binding to Gs 
		  (transducer) proteins (G refers to GTP binding)


			a. GTP dephosphorylated at the a subunit of Gs


				i. a dissociates from b and g


					(1) a binds to AC



				ii.  b and g associated with receptor



			b. free intact Gs (a,b,g) may react with receptor


				i. amplifying signal


				ii. b/g may inhibit receptor


		2. a from Gs turns on activity of Adenylate Cyclase
		   to generate production of cAMP


			a. catalyzes cAMP from ATP


				i. 4 phosphorylation sites on AC


					(1) AC made of 12 helices


					(2) amplifies signal


		3. neurotransmitters/modulators can inhibit AC/cAMP via
		  receptor Þ Gi


		4. 4 cAMP remove inhibition (2 regulatory subunits) from
		   Protein Kinase A (2)


			a. Protein Kinase A + ATP can act in three ways


				i. PKA phosphorylates (activates) a protein (enzyme)
				    which catalyzes cellular response


					(1) e.g. make or catabolize transmitter,
					   turn on active transport ...
				
				
				ii. PKA may bind to transmitter receptor (e.g. GABA)
					   to influence ion flow
				
				or
				iii. PKA passes through nuclear pores,
				     bind to and phosphorylate CREB
				    (CREB = cAMP response element binding protein) 


					(1) phosphorylated CREB binds CBP (CREB binding protein)


						(a) together CREB and CBP bind to DNA
						    and stimulate transcription


							(i)  2x CREB bind CRE
								 (cAMP response element;
								 palindrome DNA segment) 

							(ii) CBP binds RNA polymerase II
								 which binds TATA box

					(2) activates immediate-early gene products
					    like c-fos and c-jun


		5. transmitter/ modulator receptors that ® ­ cAMP:  


			a. small molecule transmitters: D1,5, b1, b2 & b3 adrenergic, 5-HT4,6,7, H2

	
			b. peptides: a-MSH, GnRH, AVP, ACTH, Gastrin, Secretin


			c.  cAMP degraded to AMP by PDE (phosphodiesterase) following
			    activation of A-kinase


	C. Gi  ¯ cAMP via inhibition of AC


		1.small molecule transmitters/receptors:


			a. amino acid: mGlu-R2,3,4,6,7,8


			b. ACh & monoamines: M2,4, D2,3,4, a2A-C, 5-HT1A,B,D,E,F


				i. a2, 5-HT1A: autoreceptors 


		2. peptides: somatostatin, endorphins, enkephalins


	D. Phospholipase C (PLC), Inositol Phosphate system


		1. transmitter/receptor ® GP ® PLC ®
					                  ¯
			2. PIP2  (phosphatidylinositol bisphosphate) - - ® IP3 (inositol trisphosphate) +  DG


		3. DG (diacylglycerol) ® Kinase C


		4. IP3 opens Ca++ channels  in membrane + endoplasmic reticulum


		5. Ca++ binds to calmodulin ® activates Ca++/calmodulin-Kinase


		6. receptors that increase inositol phosphate system:


			a. excitatory amino acid: mGlu-R1&5 


			b. ACh and monoamines: M1,3&5, H1,  a1A-D, 5-HT2A-D 


			c. peptides: NGF, EGF,TRH, OXY, GnRH,
			    AVP (V1), CCK, VIP, substance P
				
	
	E. MAP Kinase
	
	
		1. receptors that ­ MAP K:
		
		
			a. NGF-R, EGF-R, PDGF-R, NT-R


	F. Akt 
	   
	   	
		1. Neurotrophins via Akt promotes Cell Survival/block cell death

XXVII. Nitric Oxide

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