Neuronal Targets

Reelin is an extracellular matrix protein, which is secreted by neuronal cells and binds to two lipoprotein receptors (VLDLR and ApoER2) that relay the Reelin signal inside target neurons by docking the tyrosine kinase adapter disabled-1 (Dabl). This allows neurons to complete migration and adopt their ultimate positions in laminar structures in the central nervous system. In... 

Hollman, M and Heinemann, S (1994) Cloned glutamate receptors. Arm. Rev. Neurosci. 17 31-108. Lerma, J (1997) Kainate reveals its targets. Neuron 19 1155-1158. 

The cellular actions of cannabinoids clearly support the proposal that the cannabinoid receptor is inhibitory and, consequently, reduces the firing rate of target neurons. However, this is not wholly confirmed by electrophysiological measurements, which suggest that cannabinoid compounds can stimulate neurons in the hippocampus. This apparent discrepancy may be due to the ability of cannabinoids to inhibit the release of an inhibitory substance in the hippocampus and, thus, produce a net excitation. 

In contrast, pertussis toxin catalyzes the ADP-ribosyl-ation of a specific cysteine residue in Gai) G(m and Gal [1]. Only a subunits bound to their Py subunits can undergo this modification. Pertussis-toxin-mediated ADP-ribosylation inactivates these a subunits such that they cannot exchange GTP for GDP in response to receptor activation (Fig. 19-1B). By this mechanism, pertussis toxin blocks the ability of neurotransmitters to inhibit adenylyl cyclase or to influence the gating of K+ and Ca2+ channels in target neurons. However, since G is not a substrate for pertussis toxin, the toxin may not be able to block neurotransmitter-mediated inhibition of adenylyl cyclase in all cases. The Gq and Gn 16 types of G protein a subunit are not known to undergo ADP-ribosylation. 

Upregulation of the cyclic AMP pathway is one mechanism underlying opiate addiction. The mechanisms by which opiates induce tolerance, dependence and withdrawal in specific target neurons has been a major focus of research for many years. The inability to account for prominent aspects of opiate addiction solely on the basis of alterations in endogenous opioid peptides or in opiate receptors has shifted attention to postreceptor mechanisms [66]. 

Hormonal actions on target neurons are classified in terms of cellular mechanisms of action 846... 

During development, steroid-hormone receptors become evident in target neurons of the brain 854... 

Hormonal actions on target neurons are classified in terms of cellular mechanisms of action. Hormones act either via cell-surface or intracellular receptors. Peptide hormones and amino-acid derivatives, such as epinephrine, act on cell-surface receptors that do such things as open ion-channels, cause rapid electrical responses and facilitate exocytosis of hormones or neurotransmitters. Alternatively, they activate second-messenger systems at the cell membrane, such as those involving cAMP, Ca2+/ calmodulin or phosphoinositides (see Chs 20 and 24), which leads to phosphorylation of proteins inside various parts of the target cell (Fig. 52-2A). Steroid hormones and thyroid hormone, on the other hand, act on intracellular receptors in cell nuclei to regulate gene expression and protein synthesis (Fig. 52-2B). Steroid hormones can also affect cell-surface events via receptors at or near the cell surface. 

As to the primary developmental actions of testosterone, growth and differentiation appear to be involved. Testosterone or estradiol stimulates outgrowth of neurites from developing hypothalamic neurons that contain estrogen receptors [14, 15]. This is believed to be one of the principal aspects of testosterone action that increases the number and the size of neurons within specific hypothalamic nuclei in males, compared to females [1, 14, 15]. 5a-DHT may have a similar effect on androgen-sensitive neurons. Differentiation of target neurons also occurs in adult brain tissue, hormones like estradiol can evoke responses that differ between adult male and female rats [1,14,15],... 

Low doses of both indole and phenylethylamine hallucinogens potentiate the normal neophobia exhibited by rats placed into a novel environment, which typically results in an initial suppression of locomotion and investigation. These effects are extremely susceptible to the influences of ambient stimulation and handling. The action of hallucinogens on inhibitory 5-HT autoreceptors does not appear to be responsible for these effects. The relevance of either inhibitory or excitatory 5-HT receptors on target neurons to these effects of hallucinogens should be more thoroughly examined. 

The metabolic unity of the neuron requires that the same transmitter is released at all its synapses. This is known as Dale s Law (or principle) which Sir Henry Dale proposed in 1935. Dale s Law only applies to the presynaptic portion of the neuron, not the postsynaptic effects which the transmitter may have on other target neurons. For example, acetylcholine released at motor neuron terminals has an excitatory action at the motor neuron junction, whereas the same transmitter released at vagal nerve terminals has an inhibitory action on the heart. 

FIGURE 2.2 The anatomy of the neuron. Communication between two neurons occurs at the synapse. The presynaptic neuron produces and releases the neurotransmitter into the synaptic cleft. Four mechanisms (1 ) are important to understand the function of most neurotransmitter systems. The release of neurotransmitter can be modulated via presynaptic receptors (1). The amount of neurotransmitter in the synaptic cleft can be decreased by reuptake into the presynaptic neuron (2) or via enzymatic degradation. Neurotransmitter effects at the target neuron are relayed via fast-acting ion channel—coupled receptors (3) or via slower-acting G protein—coupled receptors (4). Down-stream effects of postsynaptic receptors include the phosphorylation (P) of nuclear proteins. 

An important anatomical feature of the LC is the rich innervation by afferents from the sensory systems. This puts the LC in the position to monitor the internal and external environments. The widespread LC efferents in turn then lead to an inhibition of spontaneous discharge in the target neurons. Therefore, the LC is thought to be crucial for fine-tuning the attentional matrix of the cortex and the activity in limbic structures. Anxiety disorders may be due to perturbations of this system. 

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... 

But how does the action potential bridge the gap between the axon and the target neuron The answer to this question lies at the foimda-tion of many important topics in brain chemistry. 

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