Neuropeptide receptors have undergone the same process of discovery and characterization that receptors for other neurotransmitters have enjoyed. The process begins with the pharmacological characterization of the receptor's physicochemical binding properties by assessing the affinity of various metabolically derived and synthetic peptide fragments, and the native molecule, for the receptor binding site found in membrane preparations. Peptide receptor locations are mapped with radioactive or fluorescent tags that are inserted into peptide molecules, which often contain substituted amino acids at the most vulnerable peptidase cleavage sites. Previously, once the peptide receptor was characterized pharmacologically, it was usually purified from some relatively enriched biological tissue source or brain region by affinity column chromatography. After it had been purified, binding parameters and activity were recharacterized for the reconstituted purified receptor protein and structural information obtained by X-ray crystallography. This process was closely followed in the purification of the neurotensin-neuromedin N receptor.
[...] Indeed, it has been reported that there is a marked (23 percent) decrease in the density of CRF receptors in the frontal cortex of suicide victims as compared to matched control samples; these findings have been confirmed in a second study. Somatostatin Like a number of other neuropeptides, somatostatin was serendipitously discovered during attempts to purify growth hormone- releasing factor (GRF). As the name implies, SRIF inhibits the release of growth hormone from the anterior pituitary. Since its structural identification 20 years ago, SRIF has been unequivocally shown to be the major inhibitory influence on growth hormone secretion. [...]
[...] PEPTIDASES Peptides are degraded to smaller fragments, and eventually to single amino acids, by specific enzymes termed peptidases. As yet, peptides or their fragments have not been shown to be actively taken up by presynaptic nerve terminals, as is the case for the monoamines. The enzymes may be found bound to post- or presynaptic neural membranes or in solution in the cytoplasm and extracellular fluid, and they are distributed widely in peripheral organs and serum as well as in the CNS. [...]
[...] Further evidence for distinct populations of SRIF-28 and SRIF-14 receptors is provided by their production of different second messenger effects, and their opposite effects on potassium conductance in rat cortex. Five different SRIF receptor subtypes have been identified with molecular techniques. Neuropeptide receptors have been associated with just about every type of second messenger signal transduction system that has been identified. Mechanisms using cyclic AMP; cyclic guanosine monophosphate (cGMP); protein kinases A and sodium, potassium, and calcium channels; and inositol phosphate and diacylglycerol have all been identified as neuropeptide receptor signal transduction mechanisms. [...]
[...] In the 1970s it was hypothesized that thyroid function was integral to the pathogenesis of, and recovery from, mood disorders because of the copious interactions among thyroid hormones, catecholamines, and adrenergic receptors in the CNS. Overall, these studies suggest a role for thyroid dysfunction in refractory depression and are consonant with clinical studies that suggest the existence of an increased rate of hypothyroidism among patients with refractory depression. The use of TRH as a provocative agent for assessment of hypothalamic- pituitary-thyroid axis function evolved rapidly after its isolation and synthesis. [...]
[...] The regulatory feedback of thyroid hormones onto the TRH- synthesizing neurons of the paraventricular nucleus was first demonstrated with evidence of TRH concentration changes, reported to be reduced in the median eminence after thyroidectomy, but not in the rest of the hypothalamus, and which could be prevented by thyroid hormone replacement. The treatment of normal rats with exogenous thyroid hormone decreases TRH concentration in the paraventricular nucleus and the posterior nucleus of the hypothalamus. That effect was corroborated for the TRH prohormone as well, with median eminence levels of TRH prohormone being reduced by thyroidectomy and the precursor levels increasing toward normal concentrations after thyroxine treatment. [...]
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