15. ANS NEUROTRANSMITTERS AND RECEPTORS

15. ANS NEUROTRANSMITTERS
AND RECEPTORS

• Based on the neurotransmitter they produce and release, autonomic neurons are classified as either 

1. cholinergic or 
2. adrenergic.

The receptors for the neurotransmitters 

• are integral membrane proteins located in the plasma membrane of the postsynaptic neuron or effector cell.

Cholinergic Neurons and Receptors

• Cholinergic neurons (ko¯ -lin-ER-jik) release the neurotransmitter acetylcholine (ACh). 
• In the ANS, the cholinergic neurons include 

(1) all sympathetic and parasympathetic preganglionic neurons, 

(2) sympathetic postganglionic neurons that innervate most sweat glands, and
 
(3) all parasympathetic postganglionic neurons 

• ACh is stored in synaptic vesicles and released by exocytosis.
• It then diffuses across the synaptic cleft and 
• binds with specific cholinergic receptors, integral membrane proteins in the postsynaptic plasma membrane. 

• The two types of cholinergic receptors, both of which bind ACh, are 

1. nicotinic receptors
2.  and muscarinic receptors. 

Nicotinic receptors 

• are present in the plasma membrane of dendrites and cell bodies of both sympathetic and parasympathetic postganglionic neurons , 
• the plasma membranes of chromaffin cells of the adrenal medullae,
• and in the motor end plate at the neuromuscular junction. 

• They are so named because nicotine mimics the action of ACh by binding to these receptors. 
• (Nicotine, a natural substance in tobacco leaves, is not a naturally occurring substance in humans and is not normally present in nonsmokers.) 

Muscarinic receptors 

• are present in the plasma membranes of all effectors (smooth muscle, cardiac muscle, and glands) 
• innervated by parasympathetic postganglionic axons. 
• In addition, most sweat glands receive their innervation from cholinergic sympathetic postganglionic neurons
• and possess muscarinic receptors. 

• These receptors are so named because a mushroom poison called muscarine mimics the actions of ACh by binding to them. 

• Nicotine does not activate muscarinic receptors, and
• muscarine does not activate nicotinic receptors,
• but ACh does activate both types of cholinergic receptors.

Activation of nicotinic receptors by ACh 

• causes depolarization
• and thus excitation of the postsynaptic cell, which can be a postganglionic neuron, an autonomic effector, or a skeletal muscle fiber. 

Activation of muscarinic receptors by ACh sometimes

• causes depolarization (excitation) and 
• sometimes causes hyperpolarization (inhibition), depending on which particular cell bears the muscarinic receptors. 

For example, 

• binding of ACh to muscarinic receptors inhibits (relaxes) smooth muscle sphincters in the gastrointestinal tract. 

By contrast, 

• ACh excites muscarinic receptors in smooth muscle fibers in the circular muscles of the iris of the eye, causing them to contract. 
• Because acetylcholineis quickly inactivated by the enzyme acetylcholinesterase (AChE), effects triggered by cholinergic neurons are brief.

Adrenergic Neurons and Receptors

• In the ANS, adrenergic neurons (ad -ren-ER-jik) release norepinephrine (NE), also known as noradrenalin. 
• Most sympathetic postganglionic neurons are adrenergic.

• Like ACh, NE is synthesized and stored in synaptic vesicles and
• released by exocytosis. 

• Molecules of NE diffuse across the synaptic cleft 
• and bind to specific adrenergic receptors on the postsynaptic membrane, 
• causing either excitation or inhibition of the effector cell.

• Adrenergic receptors bind both norepinephrine and epinephrine.

The norepinephrine can be 

• either released as a neurotransmitter by sympathetic postganglionic neurons 
• or released as a hormone into the blood by chromaffin cells of the adrenal medullae; epinephrine is released as a hormone. 

• The two main types of adrenergic receptors are 

1. alpha (α ) receptors and
2.  beta( β) receptors, which are found on visceral effectors innervated by most sympathetic postganglionic axons. 

• These receptors are further classified into subtypes—α 1,α  2, β 1,β2, andβ3—based on the specific responses they elicit and by their selective binding of drugs that activate or block them. 

Although there are some exceptions, 

• activation of α1 and β 1 receptors generally produces excitation, 
• and activation of α2 andβ2 receptors causes inhibition of effector tissues. 
• β 3 receptors are present only on cells of brown adipose tissue, where their activation causes thermogenesis (heat production). 

• Cells of most effectors contain either alpha or beta receptors; 
• some visceral effector cells contain both. 

• Norepinephrine stimulates alpha receptors more strongly than beta receptors;
•  epinephrine is a potent stimulator of both alpha and beta receptors.

The activity of norepinephrine at a synapse is terminated 

• either when the NE is taken up by the axon that released it 
• or when the NE is enzymatically inactivated by either

1. catechol-O-methyltransferase (COMT) 
2. or monoamine oxidase (MAO). 

• Compared to ACh, norepinephrine lingers in the synaptic cleft for a longer time. 
• Thus, effects triggered by adrenergic neurons typically are longer lasting than those triggered by cholinergic neurons.

Location and Responses of Adrenergic and Cholinergic Receptors
TYPE OF RECEPTOR	MAJOR LOCATIONS	EFFECTS OF RECEPTOR ACTIVATION
Cholinergic	Integral proteins in postsynaptic plasma membranes; activated by the neurotransmitter acetylcholine.
Nicotinic	Plasma membrane of postganglionic sympathetic and parasympathetic neurons. Chromaffin cells of adrenal medullae. Sarcolemma of skeletal muscle fibers (motor end plate).	Excitation → impulses in postganglionic neurons. Epinephrine and norepinephrine secretion. Excitation → contraction
Muscarinic	Effectors innervated by parasympathetic postganglionic neurons Sweat glands innervated by cholinergic sympathetic postganglionic neurons. Skeletal muscle blood vessels innervated by cholinergic sympathetic postganglionic neurons	In some receptors, excitation; in others, inhibition. Increased sweating. Inhibition → relaxation → vasodilation.
Adrenergic	Integral proteins in postsynaptic plasma membranes; activated by the neurotransmitter norepinephrine, and by the hormones norepinephrine and epinephrine.
α1	Smooth muscle fibers in blood vessels that serve salivary glands, skin, mucosal membranes, kidneys, and abdominal viscera; radial muscle in iris of eye; sphincter muscles of stomach and urinary bladder. Salivary gland cells. Sweat glands on palms and soles.	Excitation → contraction, which causes vasoconstriction, dilation of pupil, and closing of sphincters. Secretion of K+ and water. Increased sweating
α2	Smooth muscle fibers in some blood vessels Cells of pancreatic islets that secrete the hormone insulin (beta cells). Pancreatic acinar cells. Platelets in blood.	Inhibition → relaxation → vasodilation. Decreased insulin secretion. Inhibition of digestive enzyme secretion. Aggregation to form platelet plug.
β1	Cardiac muscle fibers. Juxtaglomerular cells of kidneys. Posterior pituitary. Adipose cells.	Excitation → increased force and rate of contraction. Renin secretion. Secretion of antidiuretic hormone. Breakdown of triglycerides → release of fatty acids into blood
β2	Smooth muscle in walls of airways; in blood vessels that serve the heart, skeletal muscle, adipose tissue, and liver; and in walls of visceral organs, such as the urinary bladder. Ciliary muscle in eye. Hepatocytes in liver.	Inhibition → relaxation, which causes dilation of airways, vasodilation, and relaxation of organ walls. Inhibition → relaxation. Glycogenolysis (breakdown of glycogen into glucose).
β3	Brown adipose tissue.	Thermogenesis (heat production).

Receptor Agonists and Antagonists

A large variety of drugs and natural products can selectively activate or block specific cholinergic or adrenergic receptors. 

• An agonist is a substance that binds to and activates a receptor, in the process mimicking the effect of a natural neurotransmitter or hormone. 

Phenylephrine, 

• an adrenergic agonist at 1 receptors,
• is a common ingredient in cold and sinus medications. 
• Because it constricts blood vessels in the nasal mucosa, 
• phenylephrine reduces production of mucus,
•  thus relieving nasal congestion.

An antagonist 

• is a substance that binds to and blocks a receptor,
• thereby preventing a natural neurotransmitter or hormone from exerting its effect. 

For example, 

atropine 

• blocks muscarinic ACh receptors, 
• dilates the pupils, 
• reduces glandular secretions, 
• and relaxes smooth muscle in the gastrointestinal tract. 
• As a result, 

1. it is used to dilate the pupils during eye examinations, 
2. in the treatment of smooth muscle disorders such as iritis and intestinal hypermotility, 
3. and as an antidote for chemical warfare agents that inactivate acetylcholinesterase.

Propranolol (Inderal®) 

• often is prescribed for patients with hypertension (high blood pressure). 
• It is a nonselective beta blocker, 
• meaning it binds to all types of beta receptors and 
• prevents their activation by epinephrine and norepinephrine.

The desired effects of propranolol are 

due to its blockade of 1 receptors—namely, 

• decreased heart rate 
• and force of contraction
• and a consequent decrease in blood pressure. 

Undesired effects

• due to blockade of 2 receptors may include 
• hypoglycemia (low blood glucose), 
• resulting from decreased glycogen breakdown
• and decreased gluconeogenesis (the conversion of a noncarbohydrate into glucose in the liver), 
• and mild bronchoconstriction (narrowing of the airways). 

• If these side effects pose a threat to the patient, a selective 1 blocker such as metoprolol (Lopressor®) can be prescribed instead of propranolol.