Adrenergic receptors (adrenoceptors)

In the sympathetic nervous system, several classes of adrenoceptors can be distinguished pharmacologically. Two families of receptors, designated α and β, were initially identified on the basis of their responses to the adrenergic agonists epinephrine, norepinephrine, and isoproterenol. The use of specific blocking drugs and the cloning of genes have revealed the molecular identities of a number of receptor subtypes. These proteins belong to a multigene family. Alterations in the primary structure of the receptors influence their affinity for various agents.

 1. α1 and α2 Receptors:

The α-adrenoceptors show a weak response to the synthetic agonist isoproterenol, but they are responsive to the naturally occurring catecholamines epinephrine and norepinephrine 

Figure : Types of adrenergic receptors.

For α receptors, the rank order of potency is epinephrine ≥ norepinephrine >> isoproterenol. The α-adrenoceptors are subdivided into two subgroups, α1 and α2, based on their affinities for α agonists and blocking drugs. For example, the α1 receptors have a higher affinity for phenylephrine than do the α2 receptors. Conversely, the drug clonidine selectively binds to α2 receptors and has less effect on α1 receptors.

a. α1 Receptors:
These receptors are present on the postsynaptic membrane of the effector organs and mediate many of the classic effects—originally designated as α-adrenergic—involving constriction of smooth muscle. Activation of α1 receptors initiates a series of reactions through a G protein activation of phospholipase C, resulting in the generation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol. IP3 initiates the release of Ca2+ from the endoplasmic reticulum into the cytosol, and DAG turns on other proteins within the cell 

Figure : Second messengers mediate  the effects of α receptors. DAG = diacylglycerol; IP3
 = inositol trisphosphate; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate.

b. α2 Receptors: 
These receptors, located primarily on presynaptic nerve endings and on other cells, such as the β cell of the pancreas, and on certain vascular smooth muscle cells, control adrenergic neuromediator and insulin output, respectively. When a sympathetic adrenergic nerve is stimulated, the released norepinephrine traverses the synaptic cleft and interacts with the α1 receptors. A portion of the released norepinephrine “circles back” and reacts with α2 receptors on the neuronal membrane.

The stimulation of the α2 receptor causes feedback inhibition of the ongoing release of norepinephrine from the stimulated adrenergic neuron. This inhibitory action decreases further output from the adrenergic neuron and serves as a local modulating mechanism for reducing sympathetic neuromediator output when there is high sympathetic activity. [Note: In this instance these receptors are acting as inhibitory autoreceptors.] 

α2 Receptors are also found on presynpatic parasympathetic neurons. Norepinephrine released from a presynaptic sympathetic neuron can diffuse to and interact with these receptors, inhibiting acetylcholine release [Note: In these instances these receptors are behaving as inhibitory heteroreceptors.] This is another local modulating mechanism to control autonomic activity in a given area. In contrast to α1 receptors, the effects of binding at α2 receptors are mediated by inhibition of adenylyl cyclase and a fall in the levels of intracellular cAMP.


c. Further subdivisions:
 The α1 and α2 receptors are further divided into α1A, α1B, α1C, and α1D and into α2A, α2B, α2C, and α2D. This extended classification is necessary for understanding the selectivity of some drugs. For example, tamsulosin is a selective α1A antagonist that is used to treat benign prostate hyperplasia. The drug is clinically useful because it targets α1A receptors found primarily in the urinary tract and prostate gland. 

2.β Receptors:

β Receptors exhibit a set of responses different from those of the α receptors. These are characterized by a strong response to isoproterenol, with less sensitivity to epinephrine and norepinephrine 

For β receptors, the rank order of potency is isoproterenol > epinephrine > norepinephrine. The β-adrenoceptors can be subdivided into three major subgroups, β1, β2, and β3, based on their affinities for adrenergic agonists and antagonists, although several others have been identified by gene cloning. [It is known that β3 receptors are involved in lipolysis but their role in other specific reactions are not known] . β1 Receptors have approximately equal affinities for epinephrine and norepinephrine, whereas β2 receptors have a higher affinity for epinephrine than for norepinephrine. Thus, tissues with a predominance of β2 receptors (such as the vasculature of skeletal muscle) are particularly responsive to the hormonal effects of circulating epinephrine released by the adrenal medulla. Binding of a neurotransmitter at any of the three β receptors results in activation of adenylyl cyclase and, therefore, increased concentrations of cAMP within the cell

3. Distribution of receptors:

Adrenergically innervated organs and tissues tend to have a predominance of one type of receptor. For example, tissues such as the vasculature to skeletal muscle have both α1 and β2 receptors, but the β2 receptors predominate. Other tissues may have one type of receptor exclusively, with practically no significant numbers of other types of adrenergic receptors. For example, the heart contains predominantly β1 receptors. 

4. Characteristic responses mediated by adrenoceptors:

It is useful to organize the physiologic responses to adrenergic stimulation according to receptor type, because many drugs preferentially stimulate or block one type of receptor. 

Figure : summarizes the most prominent effects mediated by the adrenoceptors. 

As a generalization, stimulation of α1 receptors characteristically produces vasoconstriction (particularly in skin and abdominal viscera) and an increase in total peripheral resistance and blood pressure. Conversely, stimulation of β1 receptors characteristically causes cardiac stimulation, whereas stimulation of β2 receptors produces vasodilation (in skeletal vascular beds) and bronchiolar relaxation.

5. Desensitization of receptors: 

Prolonged exposure to the catecholamines reduces the responsiveness of these receptors, a phenomenon known as desensitization. Three mechanisms have been suggested to explain this phenomenon:

 1) sequestration of the receptors so that they are unavailable for interaction with the ligand;

 2) down-regulation, that is, a disappearance of the receptors either by destruction or decreased synthesis; and

 3) an inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side by either protein kinase A or β-adrenergic receptor kinase.

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