Adrenergic receptor

The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of the catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline).

Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system. The sympathetic nervous system is responsible for the fight-or-flight response, which includes widening the pupils of the eye, mobilizing energy, and diverting blood flow from non-essential organs to skeletal muscle.

History

By the turn of the 19th century, it was agreed that the stimulation of sympathetic nerves could cause different effects on body tissues, depending on the conditions of stimulation (such as the presence or absence of some toxin). Over the first half of the 20th century, two main proposals were made to explain this phenomenon:

Beta-2 adrenergic receptor

The beta-2 adrenergic receptor (β₂ adrenoreceptor), also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that interacts with (binds) epinephrine, a hormone and neurotransmitter (ligand synonym, adrenaline) whose signaling, via a downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation. Unlike other adrenergic receptors, norepinephrine does not produce β₂ receptor stimulation.

The official symbol for the human gene encoding the β₂ adrenoreceptor is ADRB2.

Gene

The ADRB2 gene is intronless. Different polymorphic forms, point mutations, and/or downregulation of this gene are associated with nocturnal asthma, obesity and type 2 diabetes.

Structure

The 3D crystallographic structure (see figure and links to the right) of the β₂-adrenergic receptor has been determined by making a fusion protein with lysozyme to increase the hydrophilic surface area of the protein for crystal contacts.

Alpha-1 adrenergic receptor

The alpha-1 (α₁) adrenergic receptor is a G protein-coupled receptor (GPCR) associated with the G_q heterotrimeric G-protein. It consists of three highly homologous subtypes, including α_1A-, α_1B-, and α_1D-adrenergic. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α₁-adrenergic receptor in the central and peripheral nervous systems.

Effects

The α₁-adrenergic receptor has several general functions in common with the α₂-adrenergic receptor, but also has specific effects of its own. α1-receptors primarily mediate smooth muscle contraction, but have important functions elsewhere as well. The neurotransmitter noradrenaline has higher affinity for the α1 receptor than does adrenaline (which is a hormone).

Smooth muscle

In smooth muscle cells of blood vessels the principal effect of activation of these receptors is vasoconstriction. Blood vessels with α₁-adrenergic receptors are present in the skin, the sphincters of gastrointestinal system, kidney (renal artery) and brain. During the fight-or-flight response vasoconstriction results in decreased blood flow to these organs. This accounts for the pale appearance of the skin of an individual when frightened.

Alpha-2A adrenergic receptor

The alpha-2A adrenergic receptor (α_2A adrenoceptor), also known as ADRA2A, is an α₂ adrenergic receptor, and also denotes the human genome encoding it.

Receptor

α₂ adrenergic receptors include 3 highly homologous subtypes: α_2A, α_2B, and α_2C. These receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. Studies in mice revealed that both the α_2A and α_2C subtypes were required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons; the α_2A subtype inhibited transmitter release at high stimulation frequencies, whereas the α_2C subtype modulated neurotransmission at lower levels of nerve activity.

Gene

This gene encodes α_2A subtype and it contains no introns in either its coding or untranslated sequences.

Role in central nervous system

Although the pre-synaptic functions of α_2A receptors have been a major focus (see above), the majority of α₂ receptors in the brain are actually localized post-synaptically to noradrenergic terminals, and therefore aid in the function of norepinephrine. Many post-synaptic α_2A receptors have important effects on brain function; for example, α_2A receptors are localized on prefrontal cortical neurons where they regulate higher cognitive function.