Model Properties

In vitro and in vivo the somatotrophs display a striking desensitization to GRF, and as discussed in the previous section, the authors' model also exhibits this property (Fig. 2). Desensitization might occur at many stages between ligand binding to the receptors and

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Fig. 2. Model simulation showing pulsatile release of growth hormone as a consequence of pulsatile application of GRF; desensitization to repeated pulses of GRF; a complete resensitization as a result of infusion of somatostatin in the absence of pulses of GRF; almost complete inhibition of release as a result of somatostatin infusion even though the GRF pulses continue; a partial resensitization as a result of this somatostatin infusion as pulses of GRF continue. Parameters used were kl = 1, k2 = 0.002, k3 = 0.036, k4 = 1.5, k5 = 30, k6 = 5, k7 = 5, k8 = 0.5, r0 = 0.05, s0 = 0, S0 = 0.05.

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Fig. 2. Model simulation showing pulsatile release of growth hormone as a consequence of pulsatile application of GRF; desensitization to repeated pulses of GRF; a complete resensitization as a result of infusion of somatostatin in the absence of pulses of GRF; almost complete inhibition of release as a result of somatostatin infusion even though the GRF pulses continue; a partial resensitization as a result of this somatostatin infusion as pulses of GRF continue. Parameters used were kl = 1, k2 = 0.002, k3 = 0.036, k4 = 1.5, k5 = 30, k6 = 5, k7 = 5, k8 = 0.5, r0 = 0.05, s0 = 0, S0 = 0.05.

exocytosis; however, desensitization to GRF is not accompanied by desensitization to other secretagogues like GHRP6, which act via different G protein-coupled receptors and different intracellular second messenger pathways, but which also result in exocytosis via L-type channel gated calcium entry. Thus desensitization does not reflect depletion of a readily releasable pool of granules, nor inactivation of the calcium channels. In the authors' model the GRF receptor mechanism becomes transiently inactivated during sustained exposure to GRF, hence the model displays dose- and interval-dependent desensitization of growth hormone release in response to regular pulses of GRF (Figs. 3, 4). In the presence of a sufficiently high concentration of SRIF, both release of growth hormone and desensitization of the GRF receptor mechanism are less (Fig. 2); it would appear that the bound GRF receptor or the subsequent effector mechanism is transiently inactivated only if it is first functionally activated; this is equivalent to postulating a postactivation latent phase at any stage subsequent to receptor activation. A model incorporating this behavior responds to infusions of GRF with a dose-dependent release of growth hormone and desensitization of the pituitary, whereas coinfusion of SRIF results in inhibition of secretion followed by a rebound hypersecretion (Fig. 5); an "off" effect will occur in the absence of SRIF if some constitutive activation of the secretory pathway is postulated, which may be equivalent to assuming a nonzero resting level of cAMP. Interestingly, if pulses of SRIF are imposed on a background of constant GRF, the pulses result in a paradoxical dose-dependent stimulation of growth hormone release.

Fig. 3. Model simulation showing concentration-dependent desensitization to pulses of GRF.
Fig. 4. Model simulation showing interval-dependent desensitization to pulses of GRF.
Fig. 5. Model simulation showing rebound after somatostatin application, indicating the presence of constitutive activation of the GH release pathway, which partially desensitizes in the absence of somatostatin, and after application of somatostatin, resensitizes.

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