The chemical structure of the tripeptide thyrotropin- releasing hormone (TRH) is shown in Figure 1. Human preproTRH is 242 amino acids and contains six copies of the tripeptide releasing hormone within its sequence. These progenitor TRH sequences are flanked by pairs of basic amino acids (Lys-Arg or Arg-Arg), the signals for the prohormone convertases (PC) 1 and 2, the proteolytic enzymes responsible for the processing of preproTRH and proTRH as shown on the right side of Figure 2. This arrangement of the pre-prohormone is similar to that in other vertebrates that have been studied. The processing of TRH is completed by the amidation of glycine at the carboxy terminus and the modification of the N-terminal by glutaminyl cyclase to result in the mature hormone.
Fig1. The structure of thyrotropin-releasing hormone, TRH. The N-terminal pyroglutamyl moiety and the C-terminal amidation of the molecule are shown in red and yellow, respectively.
Fig2. Control of TRH gene expression and secretion. Signals from the peripheral circulation include the thyroid hormone, T3, interacting with its nuclear receptor, (TRβ) and leptin interacting with its receptor (OB-Rb). Stimulation is denoted by solid lines and inhibition by dashed lines. Neural input includes norepinephrine (NE) mediating the response to cold, and the appetite-related peptides α-MSH (melanocyte stimulating hormone), its antagonist, AgRP (Agouti-related protein), which both interact with the α-MSH receptor, MC4R; and NPY (neuropeptide Y). On the right side of the figure is shown an overview of the processing of pro-TRH by the enzymes prohormone convertases I and 2 (P1 and PC2). At the bottom of the figure are shown the hormonal and neural influences on the transcription of the TRH processing hormones, PC1 and PC2.
Figure 2 summarizes some of the regulatory influences on TRH synthesis, through transcriptional effects on the TRH gene expression and on processing through effects on the transcription of the genes for the processing enzymes, PC1 and PC2. The complexity and variety of these signals that affect TRH production are not surprising, given the multiplicity of physiological functions of thyroid hormone. Synthesis of pre-proTRH is stimulated by norepinephrine, enabling the hypothalamic-pituitary-thyroid axis to respond to cold and stress by increasing the rate of metabolism, a hallmark of thy roid hormone activity. The TRH neuron is also activated by appetite-stimulating hormones such as α-MSH and inhibited by anoretic or appetite-suppressing peptides such as AgRP (which binds to the α-MSH receptor and antagonizes its actions) and neuropeptide Y. To increase food intake, the adipose hormone leptin stimulates the TRH neuron either directly (through its receptor OB-Rb) or indirectly through the stimulation of α-MSH. Thus, the TRH neuron integrates important information about the environment relating to its effects on temperature, food intake, and stress and responds by activating the hypo thalamic-pituitary-thyroid axis. The role of peripheral hormones in the control of appetite at the level of the hypothalamus will be discussed in more detail in section VI and in Chapter 6.
Negative feedback control of TSH secretion by the peripheral hormone T3 is thought to occur primarily at the thyrotrophs in the pituitary rather than the hypothalamus, but thyroid hormones also play a role in the hypothalamic neurons.
As shown in Figure 2, T3, bound to its nuclear receptor TRβ2, inhibits the synthesis of mRNAs encoding both prepro-TRH and the enzymes that process it into mature releasing hormone.
The TRH receptor located on target cells in the anterior pituitary (as well as elsewhere in the body) is a typical GPCR (G-protein coupled receptor) of the rhodopsin family with an extracellular amino terminus, three extracellular loops, seven transmembrane regions, three intracellular loops, and an intracellular carboxyl terminus. There are two forms of the receptor, encoded by separate genes, TRH-R1 and TRH-R2. Although the two receptors differ in approximately 30% of their amino acids, three-dimensional studies indicate that the contact points between the ligand, TRH, and its binding site are the same on the two proteins. In the pituitary, TRH-R1 mediates the TRH signal through binding to Gq/11 and induction of protein kinase C (PKC)-, phosphophatidyl-inositol- and Ca2+-mediated signaling pathways.
TRH neurons have projections to areas of the central nervous system other than the anterior pituitary. A thorough discussion of these actions is not possible here, but a few illustrative examples are in order. Some axon terminals in the spinal cord have quite high TRH levels and contribute to the regulation of cardio vascular function. TRH from the dorsal motor nucleus of the vagus nerve affects gastrointestinal motility and gastric acid secretion. TRH has been identified in many peripheral tissues such as the retina, the adrenal medulla, and the pancreas, where it plays a role in the specialized functions of these cells.
