Adrenergic receptor postsynaptic

The distinction between a- and P-adrenergic receptors was first proposed by Ahlquist in 1948 based on experiments with various catecholamine derivatives to produce excitatory (a) or inhibitory (P) responses in isolated smooth muscle systems. Initially, a further subdivision into presynaptic a2- and postsynaptic oq-receptors was proposed. However, this anatomical classification of a-adrenergic recqrtor subtypes was later abandoned. 

The postsynaptic receptors on any given neuron receive information from transmitters released from another neuron. Typically, postsynaptic receptors are located on dendrites or cell bodies of neurons, but may also occur on axons or nerve terminals in the latter case, an axoaxonic synaptic relationship may cause increases or decreases in transmitter release. In contrast, autoreceptors are found on certain neurons and respond to transmitter molecules released from the same neuron. Autoreceptors may be widely distributed on the surface of the neuron. At the nerve terminal, they respond to transmitter molecules released into the synaptic cleft on the cell body, they may respond to transmitter molecules released by dendrites. Functionally, most autoreceptors appear to decrease further transmitter release in a kind of negative feedback loop. Autoreceptors have been identified for all the catecholamines, as well as for several other neurotransmitters. a2-adrenergic receptors are often found on noradrenergic nerve terminals of postganglionic sympathetic nerves, as well as on noradrenergic neurons in the CNS [36], and activation of these receptors decreases further norepinephrine release. Dopamine autoreceptors,... 

The postsynaptic S-adrenoceptors (jS-ARs) belong to the rhodopsin/ S2 adrenergic receptor-like receptors that belong to one of three major subfamilies of the GPCRs [83]. The S-AR family is subdivided into at least three discrete subtypes, the ySr, )S2-AR [84], and the atypical jSa-AR [85,86]. Additionally, a putative subtype has been identified in cardiac tissue, classified as the P4-AR [87], The P-]- and S2-AR are Gs-protein coupled, thereby elevating the intracellular level of cyclic adenosine monophosphate (cAMP) and causing positive inotropic and chronotropic effects [88]. The P2-AR can also couple to the Grprotein. 

Mechanism of Action A general anesthetic and antiemetic agent that antagonizes dopamine neurotransmission at synapses by blocking postsynaptic dopamine receptor sites partially blocks adrenergic receptor binding sites. Therapeutic Effect Produces tranquilization, antiemetic effect. 

Norepinephrine is released into the synapse from vesicles [(1) in Fig. 2.7] amphetamine facilitates this release. Norepinephrine acts in the CNS at two different types of noradrenergic receptors, the a and the P [see (2a), (2b) and (3) in Fig. 2.7]. a-Adrenergic receptors can be subdivided into receptors (coupled to phospholipase and located postsynaptically) and tt2 receptors (coupled to Gj and located primarily presynapti-cally) (Insel, 1996). P-Adrenergic receptors in the CNS are predominantly of the P subtype (3 in Fig. 2.7). P receptors are coupled to and lead to an increase in cAMP. Cyclic AMP triggers a variety of events mediated by protein kinases, including phosphorylation of the P receptor itself and regulation of gene expression via phosphorylation of transcription factors. 

The clinical effects of a2-adrenergic receptor agonists may also derive from the action of postsynaptic tt2A adrenoceptors, which modulate the excitability of target neurons in select noradrenergic terminal fields in... 

Clonidine TCA postsynaptic a - adrenergic receptor antagonism blocks the agonist effect of clonidine Decrease in hypotensive effect of clonidine can be seen within days Increased doses of clonidine to continue van Zwieten, 1975... 

As mentioned in section 4.3.3, there are two kinds of a receptor in brain and peripheral tissues. The crucial experiments have shown that brain tissue prelabeled with pH]NE will release neurotransmitter upon electrical stimulation or exposure to K+. The release is reduced by the a agonist clonidine (4.42) and stimulated by the a antagonist yohimbine (4.43). Since the adrenoreceptor involved in this latter experiment plays a vital role in modulating neurotransmitter release, it must be presynaptic and located on the nerve-ending membrane. A similar selectivity has also been shown by peripheral tissues (heart, uterus), leading to the distinction of aj (postsynaptic) and (presynaptic) adrenergic receptors. There are also presynaptic [3 receptors, which show a feedback regulation opposite to that of the ttj receptors that is, their excitation by a neurotransmitter increases NE release. 

FIGURE 12-6. Postsynaptic alpha 2 adrenergic receptors are postulated to mediate cognitive effects of norepinephrine in the frontal cortex. Direct-acting alpha 2 agonists such as clonidine and guanfacine can be helpful in attention deficit disorder, perhaps because of actions at this site. 

Since there are two primary neurotransmitters involved in autonomic discharge, there are two primary classifications of postsynaptic receptors. Cholinergic receptors are located at acetylcholine synapses, and adrenergic receptors are located at norepinephrine synapses. As indicated in Figure 18-2, each type of receptor has several subclassifications. The location and functional significance of these classifications and subclassifications are presented here. 

Clonidine acts at postsynaptic a-2 adrenergic receptors in the lower brainstem and medulla oblongata, resulting in inhibition of sympathetic discharge. This results in a decrease in cardiac output and heart rate. Following overdose, peripheral a-2 receptors may be stimulated, resulting in transient hypertension followed by hypotension. 

Phenothiazines primariiy biock postsynaptic neurotransmission by binding to dopamine (Di and D2), muscarinic, histamine Hj, and serotonergic 5-HT2 receptors. Phenothiazines also possess peripheral a-adrenergic receptor blockade and quinidine-like cardiac effects. Phenothiazines may also lower the seizure threshold. 

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