Receptors and Signal Transduction

When released from the nerve varicosities, norepinephrine interacts with specific receptors. These are collectively designated as adrenoceptors and occur on the plasma membrane of neurons from the central and peripheral nervous system or on peripheral glands or muscle cells (so-called effector cells).

The effects elicited by norepinephrine binding depend on the type of receptor. In 1948, two types of noradrenergic receptors (a and p) were described by Ahl-quist to explain the different effects of norepinephrine. To date, the a-adrenore-ceptors have been further split into two different subcategories (a1 and a2).

All three adrenoreceptor types have in common the property that they couple to G proteins and show the topology of the seven membrane-spanning domain model.

Each of the receptors can be further divided into several subtypes. Three different subtypes of the a-1 receptors (a-1A, a-1B and a-1D) have been identified, as well as three different subtypes of a-2 receptors (a-2A, a-2B and a-2C). Three further subtypes of p receptors (p1, p2 and P3) complete the catecholamine receptor family.

Table 3.10 lists the different adrenergic receptors, together with some specific agonists and antagonists to which the receptors are susceptible.

The adrenoceptors in the central nervous system are activated by norepineph-rine or by specific agonists; and signal transduction involves stimulation of G proteins. The sequence of the seven transmembrane domains is highly conserved among the three adrenoceptor subfamilies; however they share little homology in the third intracellular loop and the carboxy-terminal region.

Table 3.10 The three subfamilies of adrenergic receptors

and some

pharmacologica

l characteristics.

Subfamily

G protein

Second

Selective

Selective

Cloned

coupling

messenger

agonists

antagonists

subtypes

a1

Gq

Ca2+

Phenylephrine

Prazosine

a1A

Methoxamine

WB 4101

a1B

a1D

a2

Gi

cAMP

Clonidine

Rauwolscin

a2A

Dexmedetomi-

Yohimbine

a2B

dine

a2C

P

Gs

cAMP

Isoproterenol

Propranolol

P1

Terbutalin

Metoprolol

Pi

P3

Mutagenesis studies exploiting chimeric adrenoceptors have provided evidence that the carboxyl terminus and the third intracellular loop are important for functional binding of the ligand. A displacement of amino acids in the third intracellular loop can disturb the signal transduction downstream of the receptor site. The third intracellular loop and the carboxyl terminus are also essential for desensitization of the adrenoceptors. Desensitization occurs in the continued presence of a ligand and takes the form of a decrease in the response to the agonist over time. The mechanisms involved in desensitization of adrenoceptors include uncoupling from the G protein and removal of the receptor from the plasma membrane (so-called internalization). This internalization stops the li-gand-induced effects and allows recycling of the receptor.

The distribution of the different subtypes of adrenoceptors is not homogeneous in the brain and each receptor subtype reveals a characteristic location.

For example, in the cerebral cortex, the adrenoceptors of type a and p are differently distributed among the cortical layers. These topological differences in receptor distribution could account for the local variability of noradrenergic responses in the cortex.

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