The chromogranins and the counter-regulatory hormones: do they make homeostatic sense?

Abstract

1. The chromogranins are ubiquitous proteins which are co-stored and co-secreted with many peptide hormones. All appear to be powerful inhibitors of endocrine secretions. This poses a problem. 2. When endocrine glands are involved in the efferent limbs of homeostatic loops, they are message transmitters. The self-inhibition caused by the co-secretion of a chromogranin will, on the face of it, erase the message. 3. Pairs of counter-regulatory homeostatic hormones also present a problem. 4. If both members of the pair have clearly defined set points, as suggested by their 'time integral' (or 'growth with time') responsiveness to deviations from set point, then, if the two set points are not exactly the same, one or other member will always register an error, leading, eventually, to an overwhelmingly large and unnecessary response. 5. Our model eliminates both paradoxes, and emphasizes the importance of counter-regulation and the co-secretion of chromogranins in 'zero steady-state error' (ZSSE) homeostasis. 6. If hormone A is secreted into the blood in progressively increasing amounts when [Q], the plasma concentration of substance Q, is low, and in decreasing amounts when [Q] is high; and hormone B responds in the opposite manner, then there will be a [Q], designated [Q]p, at which the secretory rate increase, or decrease, of the two hormones is exactly the same. 7. If, in addition, the secretion of both hormones is stimulated by low plasma chromogranin levels, [Cg], but inhibited by high [Cg] then there will be a different [Q]p for every chromogranin concentration in the blood. 8. At one of these points (at a unique [Q] and [Cg]) the concentration of neither hormone will increase or decrease. This is the equilibrium point to which, according to our model, the system always returns regardless of disturbances within physiological limits. 9. This is robust ZSSE control.

Figure 1

Diagrammatic representations of the response of the parathyroid gland (A, red surface) and of the C cells of the thyroid gland (B, blue surface) to different concentrations of ionized calcium (x-axis) and chromogranin-A (CgA) (y-axis) in the plasma. The vertical z-axis denotes the rate of increase (+) or decrease (−) in the number of actively secreting endocrine cells in the parathyroid gland (A) and parafollicular cells in the thyroid gland (B). See text for further details.

Figure 2

The combination of Fig. 1A and B, depicting the response of the counter-regulatory pair of hormones concerned with zero steady-state error (ZSSE) control of the plasma ionized calcium level. Point X (where the red, blue and yellow planes intersect) is the only equilibrium point of the system. A and B are different perspectives of the same diagram. See text for further details.