2401 : Anatomy/Physiology

Transcription

1 Dr. Chris Doumen Week : Anatomy/Physiology Autonomic Nervous System TextBook Readings Pages 533 through 552 Make use of the figures in your textbook ; a picture is worth a thousand words! Work the Problems and Questions at the end of the Chapter NeuroTransmitters and Receptors Neurotransmitter are molecular triggers. They require binding to a specific receptor. Which in turn sets in motion a sequence of events that translates to a cellular event. The type of receptor determines the specificity of cellular actions. Somatic versus Autonomic In the somatic nervous system, the actual motor neuron starts in the CNS and the singular axon connects with a skeletal muscle at the neuromuscular junction. In this synapse, the neurotransmitter is released and connects with a receptor on the motor end plate ( muscle membrane area of the synapse). From previous discussion, it is known that the information handoff must be an excitatory signal. Thus, the membrane area of the skeletal muscle must experience EPSP s. This signal hand-off is accomplished by AcetylCholine and the receptor is a chemically stimulated Na+ channel, the opening of which results in a depolarization. In the autonomic system, things are a little more complicated since now we are dealing with two synapses. First synapse is in the auronomic ganglion Second synapse is at the target organ The neurotransmitters in the autonomic system are quite simple since there are only two : Acetylcholine NorEpinephrine Neurons that release Acetylcholine are called CHOLINERGIC neurons (fibers) Neurons that release NorEpinephrine ( or epinephrine) are called ADRENERGIC fibers. Similarly, receptors that bind Acetylcholine are referred to as CHOLINERGIC receptors and those that bind the catecholamines ( Norepinephrine and epinephrine) are called ADENERGIC receptors. So, in the figure below with respect to the somatic nervous system, we can say that the motor neuron is a cholinergic fiber and the receptor in the NMJ must obviously be a Cholinergic receptor. Collin County Community College District

2 Page 2 of 7 Cholinergic Receptors There are two kinds of cholinergic receptors which functionally the same because they bind Acetylcholine but are pharmacologically different because they bind other agonist molecules differently. They are in addition functionally different because the waythe receptor sets in motion cellular events. The two cholinergic receptors are Nicotinic Receptors Muscarinic Receptors Cholinergic Nicotinic Receptors They are members of a superfamily of ligand-gated membrane channels that mediate fast signal transmission at synapses. They bind nicotine (tabacco product) as an agonist molecule 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 o Binding to both sites needed for channel to open o Binding to only one site prevents channel activation These kind of receptors are found Nicotinic receptors work by means of opening Sodium and Potassium channels. Since the driving force for Sodium is larger than that for Potassium, more sodium enters than Potassium leaves. The cell thus becomes less negative and action potentials are more likely The effect of ACh via these receptors is thus always stimulatory They are found o on cell body and dendrites of all postganglionic neurons of autonomic system (PS and S) o on the hormone producing cells of adrenal medulla o and on the motor endplates of skeletal muscle (the latter ones not autonomic receptors) Note : there are distinct pharmacological differences between the somatic Nicotinic receptors (called NeuroMuscular or NM receptors) and those from the ANS (called NN receptors). This is due to differences in the subunits. For example, the NM receptors does bind alpha-bungarotoxin (viper venom) while the NN does not.

3 Page 3 of 7 Cholinergic Muscarinic Receptors Bind muscarine ( mushroom poison) Found on all effectors cells stimulated by postganglionic cholinergic fibers Muscarinic Receptors operate as G-protein coupled receptors and mediate their response by activating a variety of intra-cellular pathways. There are two importanrt system c-amp (adenylate cyclase) system PIP2 (Phosholipase C ) system The c-amp system has been described previously The PIP2 system is almost identical to the Adenylate cyclase mechanism. Instead of Adenylate cyclase being activated by G proteins, we have now Phospholipase C that becomes activated. Phospholipase C acts on a membrane class of molecules called Phosphatidyl- Inositols. The specific molecule it acts on is called phosphatidylinositol 4,5- bis-phosphate or PIP 2. Phospholipase C catalyzes the hydrolysis of PIP2 and produces produces the second messengers diacylglycerol (DAG) and inositol tris-phosphate (IP3). DAG activates Protein Kinase C which in turns phsphorylates proteins IP3 acts on the smooth ER. This result is the release of stored Calcium. Calcium in turn now becomes the activator of cellular processes

4 Page 4 of 7 There are 5 subtypes of Muscarinic receptors: M1, M2, M3, M4, M5. They all seem to work by means of G-proteins. The Effect can be stimulatory or inhibitory, depending on the kind of receptor in the target organ. M1 receptors for example act via Phospholipase C and tend to decrease the conductancefor K + ions. This thus results in a local depolarization. The M2 receptors (located in the heart) work by inhibiting Adenylate cyclase. The reduced levels of camp results in an increase in K+ conductance, resulting in local hyperpolarization M3 receptors are found in the smnooth muscles and glands of the gut and activate Phoshoplipase C (mediating contraction) M4 and M5 receptors are found in the CNS and work by inhibiting Adenyulate cyclase and activating Phospholipase respectively. The Table below shows some examples of agonists and antagonists for both Muscarinic and Nicotinic receptors. Muscarinic agents (agonists): activate muscarinic receptors They have a specific effect on the PS division They result for example in decreased heart rate, constrict pupils, contract muscles of digestive, respiratory system, urinary system Ex : Bethanechol : used to stimulate bladder after surgery Muscarinic blocking agents (antagonists): block the muscarinic receptors Once again, a specific PS action Ex : Atropine is a non-selective antagonists ( it works on al types of M receptors). It is used to decrease salivary gland activity during surgery. It is also used to counteract organophosphate poisoning. Organophosphates, such as some pesticides, destroy the activity of Ach-esterases. The over-stimulation by the abundant amount of Ach neurotransmitters is counteracted by blocking the receptors Also used for eye exams, since it prevents constriction of the smooth muscles that control pupil and iris diaphragm.

5 Page 5 of 7 The figure above shows location of receptors and neurotransmitters of the ANS. Other Drugs related to the Cholinergic receptors Nicotinic and muscarinic agents agents (agonists) : activate specific receptors Ganglionic blocking agents (antagonists): block receptors in the ganglion area; these are thus mostly nicotinic receptors These drugs can thus stimulate or inhibit both the sympathetic and parasympathetic response and are not very specific with limited use Examples of typical ganglionic antagonists are Trimethapan. It is a competitive blocker of the NN type receptor in the ganglions of the ANS. It is used to lower blood pressures in emergencies Examples of typical NM receptor antagonists are Tubocurarine and alphabungarotoxin (this last a snake venom). They both block the receptor in the neuromuscular junction and prevent ACh from binding. The result is muscle paralysis.

6 Page 6 of 7 Adrenergic Receptors (bind NE or epineprhrine) There are 2 major classes Alpha receptors : When activated, usually produce excitatory responses of smooth muscle There are subtypes : α1 and α2 A1 mostly found in smooth muscle of peripheral nervous system such as blood vessels, digestive system Example : activating these receptors will result contraction in smooth muscle of blood vessels Beta receptors When activated, usually produce inhibitory responses of smooth muscle (exception however is the heart where the beta receptors are stimulatory) There are 3 subtypes : Beta 1 : located mostly in heart tissue and the effect is increase contractility Beta 2 : located mostly in coronaries of the heart, arterioles of peripheral system and bronchi of the lungs; the effect is relaxation Beta 3 : located mostly in adipose tissue and the effect is lipolysis See the powerpoint figures and table below for details. Type Binding Action α 1 Epi > NorEpi Via PIP, increases free Ca ++ α 2 Epi > NorEpi Decreases camp β 1 Epi, NorEpi Increases camp β 2 Epi Increases camp The importance of clinical drugs and future developed drugs is to to specifically block the different subtypes of adrenergic receptors, and as such have minimal side-effects on other areas or organs of the body. Example: Alpha blockers like Prazosin HCl : used for hypertension Beta blockers like Propranolol : decrease the heart rate. However, this is a nonselective blocker and thus blocks all types of beta receptors. Not good to use when a person is suffering from asthma for example because it would prevent the bronchi from relaxing.

7 Page 7 of 7 Isoproterenol is Beta-1 agonist. Normally inhibitory, but in heart it is an excitatory component The table on the right shows some agonist/antagonist drugs with respect to the adrenergic receptors. In conclusion to the autonomic nervous system, be aware that many organs are innervated by both sympathetic and parasympathetic fibers; they thus receive dual innervation. The effect from one branch of the ANS is usually the opposite effect of the other branch. And most of the times, when one branch is activated, the activity of the other branch is decreased. This thus results in fine control of the desired activities. Look at the table/figure in your textbook to see how your sympathetic and parasympathetic system work together. For example, increased heart rate is done via the SNS on beta-1 receptors, while a heart decrease is accomplished by the PSNS via muscarinic receptors. Relaxation (dilation) of arteries and bronchi is accomplished by beta 2 receptors (SNS) but constriction in arteries works via alpha 1,2 receptors (SNS) and in the bronchi it works via a parasympathetic pathway.