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ANS NEURO-Transmitters Somatic NS • There is only one place where neurotransmitters are released since there is only one synapse ! ( Neuro muscular junction) ACh • All somatic motor neurons release Acetylcholine at their synapse with skeletal muscles. • The effect is always excitatory ! ( EPSP’s ) 1 ANS NEURO-Transmitters Autonomic NS Since we have a two neuron system, we have two synapses to deal with. 2 1 ANS NEURO-Transmitters Autonomic NS Within the ganglion, the signal needs to be transmitted from pre-ganglionic neuron to postganglionic neuron. This is similar to the somatic system and thus requires a neurotransmitter that is excitatory ! ACh The neurotransmitter released in the synapse between pre- and postganglionic neurons is always Acetylcholine. 3 ANS NEURO-Transmitters The actual functional difference between Para Sympathetic and Sympathetic Nervous system is thus at the level of the postsynaptic neuron and synapse with the effector organ ! Parasympathetic postganglionic neurons release Acetylcholine. 4 2 ANS NEURO-Transmitters Sympathetic postganglionic neurons release norepinephrine Sympathetic activation of the adrenal medulla is a special case since there is no postganglionic neuron. The activated adrenal medulla releases epinephrine and norepinephrine into the bloodstream. 5 ANS NEURO-Transmitters • Acetylcholine and Norepinephrine are thus the two major neurotransmitters released by the ANS. • ACh is released by all preganglionic neurons of PS + S and by all postganglionic PS neurons. • Postganglionic Sympathetic neurons release NE. • Neurons that release ACh are called cholinergic fibers • Neurons that release NE are called adrenergic fibers 6 3 ANS NEURO-Transmitters 7 ANS RECEPTORS The receptor, located in the cell membrane of the target cell, is a molecular transducer that sets in motion a series of cellular effects. The type of receptor determines the specificity of cellular actions. The neurotransmitter is the molecular trigger. It requires binding to the receptor before the receptor becomes activated. 8 4 ANS RECEPTORS 9 ANS RECEPTORS The two primary ligands, agonists of the ANS are thus AcetylCholine Binds to Cholinergic Receptors Norepinephrine (Epinephrine ) Binds to Adrenergic Receptors 10 5 CHOLINERGIC RECEPTORS They bind AcetylCholine Two Kinds of Receptors Nicotinic Receptors also called nAChR Muscarinic Receptors also called mAChR 11 Cholinergic Nicotinic Receptors They are members of a superfamily of ligand-gated membrane channels that mediate fast signal transmission at synapses. All nicotinic AChRs are pharmacoligically identical in that they bind nicotine as a ligand agonist. Nicotinic receptors were the first kind to be studied in detail, because they are present in high concentrations in the electrical organ that the Torpedo stingray uses to paralyze prey. 12 6 Cholinergic Nicotinic Receptors All nicotinic AChR’s are pentamers ; they consist out of 5 polypeptide subunits that are clustered around a central receptor channel. There are 2 ligand binding sites, formed by the alpha subunits and an adjacent subunit • Binding to both sites needed for channel to open • Binding to only one site prevents channel activation 13 Cholinergic Nicotinic Receptors Binding of a ligand to the receptor causes conformational changes that open the central channel to mostly Na+ and some K+ ions. What is the normal physiological ligand in the body ? AcetylCholine What occurs in the cell that has this receptor when both binding sites are occupied with ACh ? The channel opens and Na+ rushes into the cell, resulting in a depolarization ! 14 7 Cholinergic Nicotinic Receptors 15 Cholinergic Nicotinic Receptors Where do we find nicotinic Cholinergic Receptors (= nAChR)? On post-synaptic cell-membranes of synpases that experience an exocytosis of ACh from presynaptic vesicles and requiring fast depolarization of the postsynaptic area. • on the motor endplates of skeletal muscle (called somatic nAChR) • on all cell bodies and dendrites of postganglionic neurons of ParaSympathetic and Sympathetic system (called ganglionic nAChR) • on the hormone producing cells of adrenal medulla The effect of ACh on these receptors is thus always stimulatory . It causes a depolarization of the cell ! This is your typical chemically gated Na channel ! 16 8 Cholinergic Nicotinic Receptors Cholinergic nicotinic Receptor Skeletal muscle 17 Cholinergic Nicotinic Receptors Are the nACH receptors the same in the somatic system as the autonomic system ? Yes, they are similar in structure but have different proteins that make up the channel. Different proteins react differently to different drugs/toxins. So what does this mean for your system with respect to this snake venom (bungarotoxin) ? Somatic nAChR Ganglionic nAChR β4 α3 β4 Blocked by α-bungarotoxin α3 β4 Insensitive to α-bungarotoxin 18 9 Examples of nAChR effectors Epibatidine : • isolated from the skin of an Ecuadorian frog (Epipedobates tricolor) • exhibits very potent agonistic properties • Thus would induce ANS potentiation (hallucinations) and muscular spasms Curare : • isolated from the bark and leaves of the tropical plant Strychnos toxifera • it is a potent nAChR blocker in the NMJ but affects ganglionic receptors as well • the pure form is called tubocurarine ; mostly used to create muscle paralysis 19 Cholinergic Muscarinic Receptors Where do we find muscarinic Cholinergic Receptors ? On the target organs served by cholinergic postganglionic neurons ( parasympathetic nerves) ! 20 10 Cholinergic Muscarinic Receptors These receptors (mAChR) bind ACh as well, but the mechanism and response elicited by these receptors differs from previousy discussed nAChR’s. In contrast to nicotinic AChR’s, the muscarinic receptors bind Muscarine, a component derived from the fly agaric mushroom Amanita muscaria. (don’t eat the muschrooms) Muscarinic Receptors operate as G-protein coupled receptors and mediate their response by activating a variety of intra-cellular pathways. ACh + + mAChR + + = activates Enzyme Intracellular product G-protein 21 Cholinergic Muscarinic Receptors There are two Important G protein coupled systems, determined by the specific enzyme that becomes activated ( and therefore different product produced) Adenylate cyclase coupled receptors ACh AC = adenylate cyclase + mAChR + AC + ATP Cyclic AMP This is a very common pathway and is similar in for example smell and taste activation. 22 11 PLPc G-protein coupled Receptors Phospholipase C coupled receptors ACh PLPc = Phospholipase C + mAChR + + PLPc PIP2 DAG IP3 The concept of this pathway is the same, exept that a different enzyme is activated. PLPc makes two products : Diacylglycerol (DAG) and Inositol Triphosphate (IP3). 23 G-protein coupled Receptors • The purpose of these pathways is to generate intracelular signals to activate specific tissues. Those intracellular signals are the product of the activated enzymes (cAMP or DAG and IP3) • Since we are covering the ANS, keep in mind the action of sympathetic versus parasympathetic system. In this case, muscarinic receptors are typically found on target tissues of the ParaSympathetic NS ( thus the opposite actions of the Sympathetic NS). • For example, if the receptors are located in smooth muscle, the purpose is to start or inhibit smooth muscle contraction. • If the receptors are located in glands, the purpose is to start or inhibit the secretion of the glands. • If they are located in important metabolic cels, the purpose is to start or inactivate metabolic processes. 24 12 Cholinergic Muscarinic Receptors What effects do cAMP, DAG and IP3 have ? cAMP and DAG • They both activate Protein Kinases • Protein kinases in turn will phosphorylate and activate/inactivate proteins • This would be a fast way of turning on/off proteins and turn on/off a metabolic pathway IP3 • Acts on the smooth ER • Results is that calcium will be released into the cytoplasm • Calcium in turn will bind to and activate a protein called calmodulin • Activated calmodulin can now activate enzymes and other proteins 25 Cholinergic Muscarinic Receptors There are 5 different kinds of Muscarinic Receptors , named M1 to M5. Always keep in mind that these receptors are typical for parasympathetic target tissues. Location Action M2 Heart Inhibits Adenylate Cyclase (thus decreases activities) M3 Gut Smooth muscle, glands Activates PLP-C (thus mediates contraction) The M2 receptor, when it binds ACh (released from the vagus nerve), will stop production of intracellular cAMP and this is the basis for reduced heart rate and heart contraction. The M3 receptor, when it binds ACh will produce intracellular IP3 and this is the basis for increased smooth muscle contraction. Found in the constrictor muscles of the iris and smooth muscles of digestive system. 26 13 Cholinergic Muscarinic Receptors Muscarinic Antagonist: prevents activation of parasympathetic target organs ! ATROPINE : Atropa belladonna Comes from the plant Atropa belladonna. The approximate lethal dose for an adult is ten berries. Symptoms of belladonna poisoning are the same as those for atropine and include : • dilated pupils • tachycardia • dry throat • constipation • urinary retention • hallucinations, a sense of suffocation 27 Adrenergic Receptors Adrenergic receptors, also called adrenoceptors, mediate the actions of epinephrine (Adrenalin®), norepinephrine and related compounds. Adrenergic receptors are found on the target organs of the sympathetic nervous system. 28 14 Adrenergic Receptors Epinephrine and norepinephrine belong to the class of catecholamines. They are derivatives from the amino acid tyrosine ! 29 Adrenergic Receptors These receptors also are coupled to G proteins which stimulate or inhibit intracellular signalling pathways. The mechanism of signal transduction is thus very similar to the muscarinic receptors ! Epi, NorEpi AC = adenylate cyclase + Ad. R AC + + ATP Cyclic AMP Epi, NorEpi + PLPc = Phospholipase C Ad. R + + PLPc PIP2 DAG 30 IP3 15 Adrenergic Receptors Location-Action Type Location Action α1 Mostly smooth muscle of Via PLPc , increases IP3 and thus free peripheral blood vessels, eye, Ca2+ arrector pili Results in excitation, vasoconstriction , pupil dilation β1 Mostly cardiac muscle tissue and kidney β2 Smooth muscle of coronaries, bronchi β3 Adipose tissue Via Ad. Cyclase and cAMP Increased heart rate and contraction, renin release Via Ad. Cyclase and cAMP Relaxation and vasodilation Lipolysis 31 Adrenergic Receptors Alpha receptors • when activated, generally produce excitatory responses of smooth muscle in which they are located. Beta receptors • when activated, generally produce inhibitory responses of smooth muscle in which they are located. Complex physiological responses result from catecholamine stimulation because there are multiple receptor types which are differentially expressed in different tissues and cells. In addition, many of these receptors are susceptible to up and down regulation ! 32 16