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Tyrosine hydroxylase, the rate-limiting enzyme, is a substrate for PKA, PKC, and CaM kinase; phosphorylation may increase hydroxylase activity, an important acute mechanism whereby NE and Epi, acting at autoreceptors, enhance catecholamine synthesis in response to elevated nerve stimulation. In addition, there is a delayed increase in tyrosine hydroxylase gene expression after nerve stimulation, occurring at the levels of transcription, RNA processing, regulation of RNA stability, translation, and enzyme stability. Thus, multiple mechanisms maintain the content of cate-cholamines in response to increased transmitter release. In addition, tyrosine hydroxylase is subject to allosteric feedback inhibition by catecholamines.

The main features of the mechanisms of synthesis, storage, and release of catecholamines and their modifications by drugs are summarized in Figure 6-5. NE or Epi is stored in vesicles with ATP and other cotransmitters (e.g., neuropeptide Y [NPY]), depending on the site. The adrenal medulla has two distinct catecholamine-containing cell types: those with NE and those that express the enzyme phenylethanolamine-N-methyltransferase (PNMT) and contain primarily Epi (in these cells, the NE formed in the granules leaves these structures, is methylated in the cytoplasm to Epi, then reenters the chromaffin granules, where it is stored until released. In adults, Epi accounts for ~80% of the catecholamines of the adrenal medulla. A major factor that controls the rate of synthesis of Epi, and hence the size of the store available for release from the adrenal medulla, is the level of glucocorticoids secreted by the adrenal cortex. The intraadrenal portal vascular system carries the corticosteroids directly to the adrenal medullary chromaffin cells, where they induce the synthesis of PNMT (Figure 6-4). The activities of both tyrosine hydroxylase and DftH also are increased in the adrenal medulla when the secretion of glucocorticoids is stimulated. Thus, any stress that persists sufficiently to evoke an enhanced secretion of corticotropin mobilizes the appropriate hormones of both the adrenal cortex (predominantly cortisol in humans) and medulla (Epi). This relationship occurs only in certain mammals, including humans, in which adrenal chromaffin cells are enveloped by steroid-secreting cortical cells. There is evidence for PMNT expression and extra-adrenal chromaffin tissue in mammalian tissues such as brain, heart, and lung, leading to extra-adrenal Epi synthesis.

In addition to synthesis of new transmitter, NE stores are also replenished by transport of NE previously released to the extracellular fluid by the combined actions of a NE transporter (NET, or uptake 1) that terminates the synaptic actions of released NE and returns NE to the neuronal cytosol, and VMAT-2, the vesicular monoamine transporter, that refills the storage vesicles from the cytosolic pool of NE (see below). In the removal of NE from the synaptic cleft, uptake by the NET is more important than extraneuronal uptake (ENT, uptake 2). The sympathetic nerves as a whole remove ~87% of released NE via NET compared with 5% by extraneuronal ENT and 8% via diffusion to the circulation. By contrast, clearance of circulating catecholamines is primarily by nonneuronal mechanisms, with liver and kidney accounting for >60% of the clearance. Because VMAT-2 has a much higher affinity for NE than does the metabolic enzyme, monoamine oxidase, over 70% of recaptured NE is sequestered into storage vesicles.

STORAGE OF CATECHOLAMINES Vesicular storage of catecholamines ensures their regulated release and protects them from intraneuronal metabolism by oxidative deamination by monoamine oxidase (MAO) (see below and Figure 6-6). The vesicular monoamine transporter (VMAT-2) is driven by a pH gradient established by an ATP-dependent proton pump. Monoamine transporters are relatively promiscuous and transport DA, NE, Epi, and 5-HT. Reserpine inhibits VMAT-2, making the catecholamine susceptible to degradation and leading to depletion of cate-cholamine from sympathetic nerve endings and in the brain.

There are two neuronal membrane transporters for catecholamines, the NE transporter (NET) and the DA transporter (DAT) (see Table 6-5). NET is Na+-dependent and is blocked selectively by a number of drugs, including cocaine and tricyclic antidepressants such as imipramine. This transporter has a high affinity for NE and a somewhat lower affinity for Epi; the synthetic b adrenergic receptor agonist isoproterenol is not a substrate for this system. A number of other highly specific, high affinity neurotransmitter transporters have been identified, including those for 5-HT and a variety of amino acid transmitters. These plasma membrane transporters appear to have greater substrate specificity than do vesicular transporters and may be viewed as targets ("receptors") for specific drugs such as cocaine (NET, DAT) or fluoxetine (SERT, the serotonin transporter).

Certain sympathomimetic drugs (e.g., ephedrine and tyramine) produce some of their effects indirectly by displacing NE from the nerve terminals to the extracellular fluid by a nonexocytotic mechanism, and then the released NE acts at receptor sites of the effector cells. The mechanisms by which these drugs release NE from nerve endings are complex. All such drugs are substrates for NET. As a result of their transport across the neuronal membrane into the axoplasm, they make carrier

P2X,-P2X7 P2Y Y^Yg a,p

FIGURE 6-5 An adrenergic neuroeffector junction. Tyrosine is transported into the varicosity and converted to DOPA by tyrosine hydroxylase (TH) and DOPA to dopamine via the action of aromatic L-amino acid decarboxylase (AAADC). Dopamine is taken up into storage vesicles by a transporter that can be blocked by reserpine; cytoplasmic NE also can be taken up by this transporter. Dopamine is converted to NE within the vesicle via the action of dopamine-b-hydroxylase (DjSH). NE is stored in vesicles along with cotransmitters (e.g., NPY and ATP), depending on the particular neuroeffector junction; different populations of vesicles may preferentially store different proportions of the cotransmitters. Release of the transmitters occurs upon depolarization of the varicosity, which allows entry of Ca2+ through voltage-dependent Ca2+ channels. Elevated [Ca2+]ta promotes fusion of the vesicular membrane with the membrane of the varicosity, with subsequent exocytosis of transmitters. This fusion process involves the interaction of specialized proteins associated with the vesicular membrane (VAMPs, vesicle-associated membrane proteins) and the membrane of the varicosity (SNAPs, synaptosome-associated proteins). Once in the synapse, NE can interact with a- and b-adrenergic receptors to produce the characteristic response of the effector. The adrenergic receptors are GPCRs. a and b receptors also can be located presynaptically where NE can either diminish (a2), or facilitate (b) its own release and that of the cotransmitters. The principal mechanism by which NE is cleared from the synapse is via a cocaine-sensitive neuronal uptake transporter. Once transported into the cytosol, NE can be restored in the vesicle or metabolized by monoamine oxidase (MAO). NPY produces its effects by activating NPY receptors, of which there are at least five types (Yj through Y5). NPY receptors are GPCRs. NPY can modify its own release and that of the other transmitters via presynaptic receptors of the Y2 type. NPY is removed from the synapse by the action of peptidases. ATPproduces its effects by activating P2X receptors (ligand-gated ion channels) and P2Yrecep-tors (GPCRs). There are multiple subtypes of both P2X and P2Y receptors. As with the other cotransmitters, ATP can act prejunctionally to modify its own release via receptors for ATP or via its metabolic breakdown to adenosine that acts on P1 (adenosine) receptors. ATP is cleared from the synapse primarily by releasable nucleotidases (rNTPase) and by cell-fixed ectonucleotidases.

available at the inner surface of the membrane for the outward transport of NE ("facilitated exchange diffusion "). In addition, these indirect-acting sympathomimetic drugs mobilize NE stored in the vesicles by competing for the vesicular uptake process. By contrast, reserpine, which depletes vesicular stores of NE, inhibits VMAT-2, but enters the adrenergic nerve ending by passive diffusion.

Three extraneuronal transporters handle a range of endogenous and exogenous substrates (see Table 6-4). ENT, the extraneuronal amine transporter (uptake 2 or OCT3), is an organic cation transporter. Relative to NET, ENT exhibits lower affinity for catecholamines, favors Epi over NE or DA, and shows a higher maximal rate of catecholamine uptake. ENT is not Na+-dependent and h ho—<q>—c—ch2-n

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