ANS Receptors

Alpha receptors
can be classified as a subtype of adrenergic receptor, their

activation triggers a complex range of autonomic responses that will be detailed
in the following article. We recommend our readers to check our article on beta
receptors for further information on autonomic pharmacology.
Article contents:
 Alpha 1 receptors
 Alpha 2 receptors
 Drugs affecting alpha receptors
Alpha 1 receptors
The image below shows the synaptic cleft, presynaptic and postsynaptic
membranes. Alpha 1 receptors are located on the postsynaptic membrane of
effector organs.
Activation of alpha 1 receptors increases vascular smooth muscle contraction,

producing increases in blood presure. These receptors also influence activity of
genitourinary smooth muscle.
Effects of alpha 1 receptor activation on different tissues and systems:

 Vascular smooth muscle. Activation of vascular smooth muscle
receptors causes vasoconstriction, leading to an increase in peripheral resistance
and in blood pressure. Alpha 1 antagonists are used in the treatment of
hypertension because of their properties as peripheral vasodilators.
 Mydriasis. Mydriasis is mediated by both alpha 1 and 2 activation.
 Genitourinary tract smooth muscle. Alpha 1A receptors are located at
the external sphincter of the bladder. Blockade of alpha 1A receptors decreases
tone in the smooth muscle of the bladder neck and prostate, thus improving
urinary flow. Tamsulosine is used for the treatment of benign prostatic
hyperplasia because of its ability to selectively block alpha 1A receptors.
Alpha 2 receptors
Although alpha 2 receptors are found on both presynaptic neurons and

postynaptic cells, they work mainly as autoreceptors to mediate feedback
inhibition of sympathetic transmission.
In addition to neurons, alpha 2 receptors are located in other regions, like

pancreatic beta cells and platelets.
The diagram below shows how when activated, these receptors act as inhibitory
autoreceptors (they inhibit norepinephine release from adrenergic neurons) and
as inhibitory heteroreceptors (they inhibit acetylcholine release from cholinergic
neurons).
In addition, activation of alpha 2 receptors on pancreatic beta cells membranes
inhibits insulin release.
Drugs affecting alpha receptors
Alpha 1 agonists
Because of their properties as vasoconstrictive agents they are used to reduce
edema and inflammation. Common decongestant drugs include naphazoline,
phenylephrine and propylhexedrine.
Alpha 1 antagonists
These drugs act by causing vasodilation and decreased peripheral resistance,

therefore they are used in the treatment of hypertension (prazosin). Treatment of
benign prostatic hyperplasia is another clinical use of alpha 1 antagonists:
tamsulosin is a subtype-selective alpha 1A receptor that has more specificity
toward smooth muscle in genitourinary tract; thus tamsulosin has lower incidence
of orthostatic hypotension.
Alpha 2 agonists
By activating central alpha 2 receptors, alpha 2 adrenergic agonists inhibit

sympathetic outflow from CNS. Clonidine is used for the rteatment of
hypertension and symptoms associated with opioid withdrawal. Alpha-
methyldopa is a precursor to the alpha 2 agonist alpha-methylnorepinephrine, it is
the drug of choice for the treatment of hypertension during pregnancy.
Alpha 2 antagonists
Yohimbine blockade of alpha 2 receptors leads to increased release of

norepinephrine with susequent stimulation of cardiac beta 1 receptors and
peripheral vasculature alpha 1 receptors. Yohimbine was used in the past to treat
erectile dysfunction.
Beta receptors are a subtype of adrenergic receptor (adrenoceptor), their

activation triggers a sympathomimetic (adrenergic) response. This article
overviews the characteristics related to their physiology and pharmacological
aspects. In addition, a related article discusses alpha receptors.
Contents:
- Structure and general characteristics

- Location and physiology of Beta 1 Adrenergic Receptors
- Location and physiology of Beta 2 Adrenergic Receptors
- Weight control Beta 3 Adrenergic Receptors
Structure and general characteristics
Beta receptors are G-protein coupled receptors, they act by activating a Gs

protein. Gs activates adenylyl cyclase, leading to an increase in levels of
intracellular cAMP. Increased cAMP activates protein kinase A, which
phosphorylates cellular proteins.
Beta receptors are characterized by a strong response to isoproterenol, with less

sensitivity to epinephrine and norepinephrine. The rank order in terms of potency
is the following:
isoproterenol > epinephrine > norepinephrine
Beta receptors are subdivided into three subgroups, beta 1, 2, and 3. This
division is mainly based on their affinities to adrenergic agonists and antagonists.
Beta 1 receptors
Beta 1 receptors are located mainly at the heart and the kidney, their main effects
are depicted below.
Heart
- Increase in chronotropy (heart rate) and inotropy (force of contraction)
Tachycardia results from a Beta 1 mediated increase in the rate of phase 4

depolarization of sinoatrial node pacemaker cells. The inotropic effect is mediated
by increased phosphorylation of Ca ++ channels, including calcium channels in
the sarcolemma and phospholamban in the sarcoplasmatic reticulum
- Increase in AV- node conduction velocity
Beta 1 stimulated increase in Ca entry increases the rate of despolarization of AV

node cells.
Kidney
Beta 1 receptors are present mainly on yuxtaglomerular cells, where receptor

activation causes renin release.
Beta 2 receptors
In this section Beta 2 receptors will be studied in two diagrams. The first
highlights effects after Beta 2 activation in two systems (respiratory and
reproductive), this is viewed separately because of the clinical relevance of Beta
2 agonists in clinical practice. The second figure shows the remaining
sympathomimetic effects elicited by Beta 2 receptor activation in other systems.
Bronchial smooth muscle
Beta 2 receptor activation promotes bronchodilation, this physiological property

is enhanced by inhaled Beta 2 agonists used in the treatment of asthma and
COPD. Some drugs under this category include: salbutamol (albuterol in the US),
salmeterol, formoterol and terbutaline.
Uterine contraction
Drugs that bind to Beta 2 receptors (Beta 2 agonists) are used in the treatment of
premature labour, this clinical application illustrates how Beta 2 receptors
mediate tocolysis on the uterine muscle. Ritodrine is an example of a tocolytic
drug.
Bladder detrusor muscle: adrenergic activation of Beta 2 receptors at the
bladder promotesrelaxation. Bladder constriction is activated by the
parasympathetic system, therefore drugs that activate muscarinic receptors such
as bethanechol are used in the treatment of urinary retention.
Eye ciliary muscle: this muscle controls eye accomodation and regulates the
flow of aqueous humour. Its sympathetic innervation is mediated by Beta 2
receptors.
GI tract: adrenergic activation of the gastrointestinal tract produces a slowing of

peristaltic movements (decreased motility) and secretions. These changes are
mediated by Beta 2 receptors.
Liver: hyperglycemia and lipolysis occur when Beta 2 receptors are activated.

Glucose metabolism is potentiated through gluconeogenesis and glycogenolysis.
Vascular smooth muscle: while Alpha 1 receptors mediate vasoconstriction,

Beta 2 receptors induce vasodilation in muscle and liver.
Beta 3 receptors
It has been recently proposed that Beta 3 receptors are linked to the regulation
of body weight.Located mainly in adipose tissue, Beta 3 receptors promote
lipolysis.
ACETYLCHOLINE RECEPTORS:
A number of drugs target acetylcholine receptors, blockade of these receptors is

associated with anticholinergic (parasympatholytic) effect, while stimulation
causes activation of cholinergic (parasympathomimetic) effects.
This articles overviews the key concepts on the pharmacology of acetylcholine

receptors, such as:
What happens after acetylcholine is released?
Classification of acetylcholine receptors
Location
Acetylcholine receptors and the autonomic nervous system
Muscarinic receptors
Nicotinic receptors
What happens after acetylcholine is released?
Acetylcholine is released from a presynaptic neuron into the synaptic cleft. Once
in the synaptic gap, acetylcholine can:
- Bind to presynaptic receptors: presynaptic activation or inhibition leads to

automodulation of the presynaptic cholinergic neuron.
- Be degradated by acetylcholinesterase: activity of this enzime on acetylcholine

triggers its degradation into choline and acetyl coenzime A, thus terminating its
effect.
- Bind to postsynaptic receptors: activation of these receptors by acetylcholine
leads to cholinergic response.
Classification of acetylcholine receptors
The figure below shows the two main families of acetylcholine receptors:
muscarinic and nicotinic. In structural terms, muscarinic receptors are G-coupled
protein receptors, while nicotinic receptors are ligand-gated ion channels. They
can be found on both sides of the synaptic cleft (presynaptic and postsynaptic).
However, for clinical purposes, we are focusing only on postsynaptic receptors.
Location of acetylcholine receptors
Acetylcholine is a key neurotransmitter acting on a wide number of functions and

tissues. This figure shows the three main locations of acetylcholine receptors:
CNS receptors
(muscarinic and nicotinic): cholinergic neurotransmission at the CNS level is
thought to regulate sleep, wakefulness, and memory. Two clinical situations
depict the role of acetylcholine in CNS:
- Acetylcholinesterase inhibitors are used in the treament of Alzheimer’s disease

and other dementias. Inhibition of the enzime that catalyzes acetylcholine
degradation (acetylcholinesterase) produces an increased concentration of
acetylcholine at the synaptic cleft, thus potentiating cholinergic
neurotransmission. Examples of these drugs include donepezil and rivastigmine.
- Drugs that possess anticholinergic properties may cause acute encephalopathy,

such as delirium or a confusional state. Some over-the-counter medications such
as diphenidramine (an antihistamine) can cause cholinergic blockade that may
lead to a decompensation of underlying cognitive, functional and behavioral
deficits (particularly in patients with Alzheimer’s disease).
Autonomic receptors: they are present both in adrenergic and cholinergic

transmission. They are discussed in the next section.
Neuromuscular junction: acetylcholine receptors at the neuromuscular

junction are exclusively nicotinic, they belong to the NN subtype.
Acetylcholine receptors and the autonomic nervous

system
Acethylcholine acts on central and peripheral nervous systems ( the latter is

divided into somatic and autonomic). The autonomic nervous system (ANS)
exerts its actions through its two antagonic branches: sympathetic ( adrenergic)
and parasympathetic (cholinergic).
Looking the diagram below we can see that both sympathetic and
parasympathetic branches are modulated at the preganglionic level by the
neurotransmitter acetylcholine. This molecule binds nicotinic receptors at the
autonomic ganglia to trigger the release of norepinephrine (if a sympathetic
synapse is stimulated) or acetylcholine that binds to tissue muscarinic receptors,
which will produce a parasympathetic or cholinergic response.
Muscarinic receptors
Muscarinic receptors bind both acetylcholine and muscarine, an alkaloid present

in certain poisonous mushrooms (it was first isolated in Amanita muscaria).
Cholinergic transmission (acetylcholine-mediated) that activates muscarinic
receptors occurs mainly at autonomic ganglia, organs innervated by the
parasympathetic division of the autonomic nervous system and in the central
nervous system.
All muscarinic receptors are G-protein coupled receptors. Binding studies have

identified five subclasses of muscarinic receptors: M1,M2, M3, M4, and M5. The
image below shows their locations:
M1, M4 and M5 receptors: CNS. These receptors are involved in complex CNS
responses such as memory, arousal, attention and analgesia. M1 receptors are
also found at gastric parietal cells and autonomic ganglia.
M2 receptors: heart. Activation of M2 receptors lowers conduction velocity at

sinoatrial and atrioventricular nodes, thus lowering heart rate.
M3 receptors: smooth muscle. Activation of M3 receptors at the smooth muscle

level produces responses on a variety of organs that include: bronchial tissue,
bladder, exocrine glands, among others.
Nicotinic receptors
Unlike muscarinic receptors (which are G-protein coupled receptors), nicotinic

receptors are ligand-gated ion channels. When bound to acetylcholine , these
receptors undergo a conformational change that allows the entry of sodium ions,
resulting in the depolarization of the effector cell.
Nicotinic receptors can be divided as the diagram shows:

N1 or NM receptors: these receptors are located at the
neuromuscular junction, acetylcholine receptors of the NM subtype are the only
acetylcholine receptors that can be found at the neuromuscular junction.
N2 or NN receptors: as mentioned before, nicotinic receptors play a key role in

the transmission of cholinergic signals in the autonomic nervous systems.
Nicotinic receptors of the NN subtipe can be found both at cholinergic and
adrenergic ganglia, but not at the target tissues (e.g, heart, bladder, etc). These
receptors are also present in the CNS and adrenal medulla.

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Alpha receptors

can be classified as a subtype of adrenergic receptor, their

Activation of alpha 1 receptors increases vascular smooth muscle contraction,

Effects of alpha 1 receptor activation on different tissues and systems:

Although alpha 2 receptors are found on both presynaptic neurons and

In addition to neurons, alpha 2 receptors are located in other regions, like

These drugs act by causing vasodilation and decreased peripheral resistance,

By activating central alpha 2 receptors, alpha 2 adrenergic agonists inhibit

Yohimbine blockade of alpha 2 receptors leads to increased release of

Beta receptors are a subtype of adrenergic receptor (adrenoceptor), their

- Structure and general characteristics

Beta receptors are G-protein coupled receptors, they act by activating a Gs

Beta receptors are characterized by a strong response to isoproterenol, with less

isoproterenol > epinephrine > norepinephrine

- Increase in chronotropy (heart rate) and inotropy (force of contraction)

Tachycardia results from a Beta 1 mediated increase in the rate of phase 4

- Increase in AV- node conduction velocity

Beta 1 stimulated increase in Ca entry increases the rate of despolarization of AV

Beta 1 receptors are present mainly on yuxtaglomerular cells, where receptor

Bronchial smooth muscle

Beta 2 receptor activation promotes bronchodilation, this physiological property

GI tract: adrenergic activation of the gastrointestinal tract produces a slowing of

Liver: hyperglycemia and lipolysis occur when Beta 2 receptors are activated.

Vascular smooth muscle: while Alpha 1 receptors mediate vasoconstriction,

A number of drugs target acetylcholine receptors, blockade of these receptors is

This articles overviews the key concepts on the pharmacology of acetylcholine

What happens after acetylcholine is released?

Classification of acetylcholine receptors

Acetylcholine receptors and the autonomic nervous system

What happens after acetylcholine is released?

- Bind to presynaptic receptors: presynaptic activation or inhibition leads to

- Be degradated by acetylcholinesterase: activity of this enzime on acetylcholine

Classification of acetylcholine receptors

Location of acetylcholine receptors

Acetylcholine is a key neurotransmitter acting on a wide number of functions and

- Acetylcholinesterase inhibitors are used in the treament of Alzheimer’s disease

- Drugs that possess anticholinergic properties may cause acute encephalopathy,

Autonomic receptors: they are present both in adrenergic and cholinergic

Neuromuscular junction: acetylcholine receptors at the neuromuscular

Acetylcholine receptors and the autonomic nervous

Acethylcholine acts on central and peripheral nervous systems ( the latter is

Muscarinic receptors bind both acetylcholine and muscarine, an alkaloid present

All muscarinic receptors are G-protein coupled receptors. Binding studies have

M2 receptors: heart. Activation of M2 receptors lowers conduction velocity at

M3 receptors: smooth muscle. Activation of M3 receptors at the smooth muscle

Unlike muscarinic receptors (which are G-protein coupled receptors), nicotinic

Nicotinic receptors can be divided as the diagram shows:

N2 or NN receptors: as mentioned before, nicotinic receptors play a key role in

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