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Autonomic Nervous System II

Page history last edited by PBworks 14 years, 2 months ago

Autonomic Nervous System II:

Membrane receptors, Second messengers, and Signal Transduction pathways.

 

  • A. Cholinergic receptors (Muscarinic and Nicotinic).

 

Receptor subtypes for ACh: ACh binds to two types of cholinergic receptors. They are nicotinic (stimulated by nicotine) and muscarinic (stimulated by muscarine) receptors. Nicotinic receptors are present in the cell body of postganglionic neurons of the autonomic ganglia whereas muscarinic receptors are present on the effector cells of cardiac, smooth muscle, and glands. The cellular mechanisms by which ACh produces its effects are different for nicotinic and muscarinic receptors.


Molecular structure of the nicotinic cholinergic receptor.Side View (left), and a cross sectional view of an electron-density map of the receptor (right). The hole in the center is the mouth of the channel through which Na and K enters (from Unwin et al. 1988).


Nicotinic receptor is a ligand-gated, non-selective cation channel. When ACh binds to the receptor, the ion channel opens and allows rapid movement of Na+ and K+ across the membrane, leading to depolarization and excitation.

 

Muscarinic receptor in the cell membrane are linked to a GTP-binding (G) protein. When ACh binds to the extracellular site of the muscarinic receptor protein, a conformational change occurs within the receptor molecule causing "activation" of the G protein that is coupled to the receptor (see part B). The G protein then either stimulates or inhibits other intracellular effectors such as enzymes or ion channels, producing a physiological response. For example, in atrial cells, ACh released from the vagus nerve binds to the muscarinic receptor, and the activated G protein then opens K channels, causing hyperpolarization and slowing of the heart rate. There are now five subtypes of muscarinic receptors (M1-M5). Different muscarinic receptors are coupled to different effectors within a cell. Thus, a simple molecule like ACh has the potential to produce a variety of physiological responses in different cell types, depending on which effector is coupled to which muscarinic receptor subtype.



 

  • B.Adrenergic receptors

 

Receptor subtypes for NE: Adrenergic receptors consist of alpha (A) and beta (B) subtypes: A1, A2, B1, and B2. Molecular biological methods have identified additional subtypes of A and B receptors such as A1a, A1b, etc. At this juncture, you only need to know the four major types of receptors (A1, A2, B1, and B2). Different adrenergic receptors belong to a family of closely related integral membrane glycoproteins. Many of these proteins have been purified and cloned, and current studies are focused on identifying the functions of these proteins in signal transduction pathways. We now know that NE binds to A1, A2, and B1 adrenergic receptors, and that E (epinephrine) binds to A1, A2, B1 and B2 receptors.


Topographical representation of the primary sequence of the human B2-adrenergic receptor. The receptor protein has seven hydrophobic regions each capable of spanning the plasma membrane. There are extracellular and intracellular loops, and extracellular amino terminus and a cytoplasmic carboxy terminal region. Many other membrane receptors have similar topological protein structure. These include muscarinic receptors, and all types of adrenergic receptors.



It is important to note that an intracellular second messenger such as cAMP can produce a variety of effects. For example, a rise in [cAMP] will increase contractile force in heart cells but decrease it in smooth muscle cells via different cellular mechanisms.

 

In nerves, A1 and A2 adrenergic receptors are usually located in postsynaptic and presynaptic membranes, respectively. Stimulation of the A2 receptors by NE results in reduction of neurotransmitter release from the presynaptic terminal by antagonizing the depolarization produced by nerve action potentials arriving at the presynaptic terminal. A1 and A2 receptors are also present in various effector organs tissues such as smooth muscle, heart muscle, platelets, pancreatic B cells and liver. B1-adrenergic receptors are present in heart cells and juxtaglomerular cells. B2-adrenergic receptors are present in smooth muscle, skeletal muscle and liver among others.

 

  • C. G proteins and second messengers


At rest (basal state) in the absence of an agonist, GDP is bound to the A subunit of the G protein which is a ABG heterotrimer. When an agonist binds the receptor, the GTP in the cell replaces GDP in the presence of Mg2+ as co-factor. This causes dissociation of the A subunit from BG subunit. These two subunits (A-GTP and BG) then serve as second messengers in regulating the activity of cellular effectors such as ion channels and enzymes. Some effectors are regulated by A, some by BG and some by both subunits. An example of an ion channel that is activated by BG subunit is the atrial muscarinic K+ channel.


Actions of the ANS on the cardiovascular system

 

  • A. Heart

Parasympathetic:

 

1. SA Node: ACh binds to muscarinic receptors and stimulates Gi protein in the pacemaker (and also atrial) cells. The BG subunit of Gi protein interacts with a specific population of K+ channels called the muscarinic-gated K+ channels, and opens them. Increased permeability of the membrane to K+ leads to decreased pacemaker potential (reduced spontaneous depolarization), leading to reduced heart rate. It has also been shown that Na+ permeability is reduced upon muscarinic receptor stimulation due to inhibition of If. This would also help to reduce the heart rate. If is a cyclic nucleotide-gated channel responsible for the pacemaker activity, and is directly gated by cAMP that is produced by adenylyl cyclase.

 

2. Ventricle: Very little or no effect due to lack of parasympathetic innervation

 

Sympathetic:

 

1. SA Node: NE (agonist for A1, A2 and B1 receptors) binds to B1 receptors in the cardiac cell membrane. This includes both atrial and ventricular muscle. The activated G proteins (Gs type) interact with adenylyl cyclase to generate cAMP from ATP. cAMP activates a protein kinase (protein Kinase A) that phosphorylates Na+ and Ca2+ channels. Phosphorylation by protein kinase A leads to increased probability of opening of these channels, producing an increased rate of spontaneous depolarization in pacemaker cells and an increased heart rate. NE also increases If and thereby helps to increase heart rate.

 

2. Atria and Ventricle:

In atrial and ventricular cells, phosphorylation of Ca2+ channels leads to increased influx of Ca2+ into the cell, leading to an increase in the force of contraction is increased. The overall effect of NE is increased heart rate and contractility.

 

  • B. Blood Vessels (arteries arterioles and veins)

 

Parasympathetic:

1. Cholinergic innervation is restricted in distribution

a. External genitalia

b. Certain cranial arteries

Except for the blood vessels in external genitalia and certain cranial arteries, the parasympathetic system does not innervate the blood vessels, and therefore does not normally play a physiological role in vasoconstriction or vasodilatation. However, if ACh is injected into the blood, relaxation of the smooth muscle in the arterioles and a fall in blood pressure occur. This is due to the effect of ACh on endothelial cells of the blood vessels. Endothelial cells release EDRF (endothelial-derived relaxation factor=nitric oxide [NO]) which diffuses to the smooth muscle cells and activates guanylyl cyclase. This leads to an increase in cGMP level in the cell. A cGMP-dependent protein kinase is activated and ultimately results in dephosphorylation of myosin light chain, causing relaxation. It is also believed that cGMP reduces Ca2+ in the cell and increases K+ permeability, both of which would contribute to vasorelaxation. The mechanism by which ACh causes relaxation of smooth muscles in external genitalia and certain cranial arteries is the same, i.e., via formation of NO.

 

Synthesis and action of NO

Organic nitrates such as nitroglycerin are used in the treatment of angina pectoris caused by ischemic heart disease. These agents lead to the formation of nitric oxide (NO) when administered to the body. The vasorelaxation produced by NO increases the blood supply to the ischemic myocardium, and decreases oxygen consumption by the muscle.

 

NO is a soluble, odorless, colorless gas that is highly reactive. NO is now known to be involved in many biological functions such as in the immune system, neuronal signaling, memory, angiogenesis, apoptosis, and even light flashes of the firefly.

 

Sympathetic:

 

1. Sympathetic adrenergic:

 

Norepinephrine released from postganglionic nerve fibers binds to A1 receptors and produces smooth muscle contraction. This occurs as a result of formation of inositol trisphosphate (IP3) from the action of phospholipase C (PLC) on phosphatidylinositol-4,5-bisphosphate in the membrane. IP3 releases Ca2+ from intracellular stores such as endoplasmic reticulum and elevates basal Ca2+ concentration in smooth muscle cells. An increase in Ca2+ leads to increased contraction. Diacylglycerol, also formed by the action of PLC, has a relatively minor role on smooth muscle contraction compared with that produced by IP3.

 

Arterioles, arteries and veins normally maintain a certain degree of basal tone even in the absence of sympathetic input. An increase in sympathetic nerve activity causes the smooth muscle to contract and raises the total peripheral resistance and blood pressure.

 

During exercise or during fight-fright response (defense behaviors), epinephrine is secreted by the adrenal medulla of the adrenal gland. Epinephrine binds to B2 receptors in the arterioles of skeletal muscle, and cause relaxation of the smooth muscle via myosin light chain kinase (MLCK; see diagram). Protein kinase A activated by cAMP phosphorylates MLCK. This causes a reduction of its affinity for Ca-CaM, resulting in less active MLCK. This leads to relaxation (or less contraction) of the smooth muscle. The blood flow to the skeletal muscle is thus increased in preparation for running or fighting.

 

Epinephrine also alters the metabolic state by increasing glycogenolysis in liver and skeletal muscle to provide energy. Increased glycogen breakdown is a result of activation of phosphorylase by cAMP via phosphorylase kinase.



2. Sympathetic cholinergic: Skeletal muscle vascular beds and sweat glands.

 

a. normally inactive

b. activated during defense reaction

In addition to the vasodilatory action of sympathetic system in the skeletal muscle, several local mechanisms are involved in increasing blood flow to the skeletal muscle during exercise. These mechanisms include fall in tissue PO2, rise in PCO2, accumulation of K, change in pH (acid) and a rise in temperature. These local autoregulatory mechanisms become more important in blood flow control during exercise.

 

Useful generalizations:

 

Acetylcholine binding to muscarinic receptors (M1 type) in smooth muscle produces contraction.

 

Examples:

  • 1.Contraction of gastrointestinal wall smooth muscle
  • 2.Contraction of the detrusor muscle of urinary bladder for emptying during urination
  • 3.Contraction of ciliary smooth muscle makes the lens more spherical (near vision)
  • 4.Contraction of sphincter muscle of iris (miosis)

 

Norepinephrine binding to A1 receptors in smooth muscle produces contraction.

 

Examples:

  • 1. Contraction of arteriolar smooth muscle
  • 2. Contraction of sphincters in the gastrointestinal tract
  • 3. Contraction of radial muscle of iris (mydriasis)
  • 4. Contraction of bronchial smooth muscle

 

Epinephrine binding to B2 receptors in smooth muscle produces relaxation

 

Examples:

  • 1. Relaxation of arteriolar smooth muscle
  • 2. Relaxation of bronchial smooth muscle
  • 3. Relaxation of detrusor muscle of urinary bladder

 

Norepinephrine (NE) binding to A2 receptors on the presynaptic terminal reduces firing rate of neurons and thus reduce neurotransmitter release. This is one mechanism by which NE has an inhibitory effect on gastrointestinal motility.

 

Norepinephrine binding to B1 receptors in cardiac muscle produce increased force and rate of contraction. ACh binding to M2 receptors in the heart slows heart rate.



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