Receptors and Signal Transduction

Three different receptor subtypes, termed H1, H2 and H3, bind histamine specifically. The three receptor subtypes can be distinguished by their different binding patterns and different biological effects (Table 3.9). All three receptor subtypes seem to belong to the superfamily of G protein-coupled receptors.

Table 3.9 The three different subtypes of histamine receptors and some of their characteristic functional features.

Subtype of histamine receptor

Table 3.9 The three different subtypes of histamine receptors and some of their characteristic functional features.

Subtype of histamine receptor

HT

h2

H3

Localization on

3p2

5

?

human chromosome

Specific agonist

(Trifluoromethyl

Impromidine

(R)a-Methyl-histamine

phenyl)-histamine

Specific antagonist

Mepyramine

Cimetidine

Thioperamide

autoreceptor

No

No

Yes

Receptor localization

Postsynaptic

Postsynaptic

Presynaptic

G protein coupling

Gi/o

Gs

Gi/o

Highest densities

Cerebellum,

Caudate-putamen,

Frontal cortex, caudate-

thalamus,

cerebral cortex,

putamen, substantia

hippocampus

amygdala

nigra

118 | 3 Neurotransmitters H1 receptors

The H1 receptor is a glycoprotein of about 490 amino acids. Antagonists of the H1 receptor are collectively known as "antihistamines" (which are capable of crossing the blood-brain barrier). The activation of the H1 receptor gives rise to a variety of intracellular signals, which depend on the action of a G protein of the type Gq. This G protein enhances phospholipase C activation, which ultimately leads to activation of the DAG/IP3 pathway and consequent release of Ca2+ from intracellular calcium stores.

The activation of H1 receptors is positively coupled to an enhancement in phospholipid turnover and stimulates glycogen hydrolysis. Prolonged exposure of the receptor to its neurotransmitter can produce receptor subsensitivity (de-sensitization). The molecular nature of the desensitization effect is not known.

Agonists of the H1 receptor are substances like 2,3 (trifluoromethyl)-phenyl-histamine, 2-methylhistamine and 2-(pyridyl)-ethylamine. In addition, different specific antagonists have been found which interact with the H1 receptors. Some of these antagonists have been used in the treatment of allergies, but since they cross the blood-brain barrier they exhibit side-effects within the central nervous system, predominantly tranquilizing effects, by inhibition of cerebral H1 receptors. Therefore, considerable efforts have been made to develop H1 receptor antagonists which do not cross the blood-brain barrier and so are without a sedative effect.

H1 receptors are mainly found in cerebral areas, in which histaminergic terminals are present at high densities. H1 receptor-expressing cells have been identified in the pyramidal layer of the hippocampus and in cerebellar Purkinje cells.

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