Klaus Prank

Pulsatile patterns in hormone secretion

Endocrine systems are regulated dynamically. With the development of sensitive methods for hormone measurements and high-frequency blood sampling, it has been shown in many endocrine systems that hormonal information is encoded in distinct pulses varying in frequency from minutes to hours. Focusing on pituitary hormones as an example, this review discusses the relevance of this pulsatile pattern of secretion on the regulation of endocrine systems and its implications on diagnosis and therapy o f endocrine diseases.

Coding efficiency and information rates in transmembrane signaling

A variety of cell types responds to hormonal stimuli by repetitive spikes in the intracellular concentration of calcium ([Ca(2+)](i)) which have been demonstrated to encode information in their frequency, amplitude, and duration. These [Ca(2+)](i)-spike trains are able to specifically regulate distinct cellular functions. Using a mathematical model for receptor-controlled [Ca(2+)](i) oscillations in hepatocytes we investigate the encoding of fluctuating hormonal signals in [Ca(2+)](i)-spike trains. The transmembrane information transfer is quantified by using an information-theoretic reverse-engineering approach which allows to reconstruct the dynamic hormonal stimulus from the [Ca(2+)](i)-spike trains. This approach allows to estimate the accuracy of coding as well as the rate of transmembrane information transfer. We found that up to 87% of the dynamic stimulus information can be encoded in the [Ca(2+)](i)-spike train at a maximum information transfer rate of 1.1 bit per [Ca(2+)](i)-spike. These numerical results for humoral information transfer are in the same order as in a number of sensory neuronal systems despite several orders of magnitude different time scales of operation suggesting a universal principle of information processing in both biological systems.

Time series prediction of plasma hormone concentration. Evidence for differences in predictability of parathyroid hormone secretion between osteoporotic patients and normal controls.

Recent evidence links osteoporosis, a disease of bone remodeling, to changes in the dynamics of parathyroid hormone secretion. We use nonlinear and linear time series prediction to characterize the secretory dynamics of parathyroid hormone in both healthy human subjects and patients with osteoporosis. Osteoporotic patients appear to lack the periods of high predictability found in normal humans. Our results may provide an explanation for why an intermittent administration of parathyroid hormone is effective in restoring bone mass in osteoporotic patients.

Circadian changes in pulsatile TSH release in primary hypothyroidism

OBJECTIVE We evaluated pulsatile and circadian TSH secretion in primary hypothyroidism.

Central Nervous System Control of Thyrotropin Secretion during Sleep and Wakefulness

Thyrotropin (TSH) is a pulsatile secreted hormone with a pronounced circadian rhythmicity and a characteristic nightly surge based on an augmentation of pulsatile release. A number of physiological factors influence TSH secretion via an alteration in the amount of pulsatile released hormone. An increase in somatostatinergic tone during fasting appears to decrease TSH pulse amplitude and sequentially mean TSH serum levels. In contrast, blockade of dopaminergic tone by metoclopramide infusion when circulating TSH levels are low during the afternoon hours increase TSH pulse amplitude to levels comparable to the nightly TSH surge suggesting a physiological dampening of TSH pulse amplitude by dopamine during the daytime.

Predictive neural networks for learning the time course of blood glucose levels from the complex interaction of counterregulatory hormones

Diabetes mellitus is a widespread disease associated with an impaired hormonal regulation of normal blood glucose levels. Patients with insulin-dependent diabetes mellitus (IDDM) who practice conventional insulin therapy are at risk of developing hypoglycemia (low levels of blood glucose), which can lead to severe dysfunction of the central nervous system. In large retrospective studies, up to approximately 4 of deaths of patients with IDDM have been attributed to hypoglycemia (Cryer, Fisher, & Shamoon, 1994; Tunbridge, 1981; Deckert, Poulson, & Larsen, 1978). Thus, a better understanding of the complex hormonal interaction preventing hypoglycemia is crucial for treatment. Experimental data from a study on insulin-induced hypoglycemia in healthy subjects are used to demonstrate that feedforward neural networks are capable of predicting the time course of blood glucose levels from the complex interaction of glucose counterregulatory (glucose-raising) hormones and insulin. By simulating the deficiency of single hormonal factors in this regulatory network, we found that the predictive impact of glucagon, epinephrine, and growth hormone secretion, but not of cortisol and norepinephrine, were dominant in restoring normal levels of blood glucose following hypoglycemia.

Noise enhanced hormonal signal transduction through intracellular calcium oscillations

In a wide range of non-linear dynamical systems, noise may enhance the detection of weak deterministic input signals. Here, we demonstrate this phenomenon for transmembrane signaling in a hormonal model system of intracellular Ca(2+) oscillations. Adding Gaussian noise to a subthreshold extracellular pulsatile stimulus increased the sensitivity in the dose-response relation of the Ca(2+) oscillations compared to the same noise signal added as a constant mean level. These findings may have important physiological consequences for the operation of hormonal and other physiological signal transduction systems close to the threshold level.

Self-organized segmentation of time series: separating growth hormone secretion in acromegaly from normal controls.

The pulsatile pattern of growth hormone (GH) secretion was assessed by sampling blood every 10 min over 24 h in healthy subjects (n = 10) under normal food intake and under fasting conditions (n = 6) and in patients with a GH-producing tumor (acromegaly, n = 6), before and after treatment with the somatostatin analog octreotide. Using autocorrelation, we found no consistent separation in the temporal dynamics of GH secretion in healthy controls and acromegalic patients. Time series prediction based on a single neural network has recently been demonstrated to separate the secretory dynamics of parathyroid hormone in healthy controls from osteoporotic patients. To better distinguish the differences in GH dynamics in healthy subjects and patients, we tested time series predictions based on a single neural network and a more refined system of multiple neural networks acting in parallel (adaptive mixtures of local experts). Both approaches significantly separated GH dynamics under the various conditions. By performing a self-organized segmentation of the alternating phases of secretory bursts and quiescence of GH, we significantly improved the performance of the multiple network system over that of the single network. It thus may represent a potential tool for characterizing alterations of the dynamic regulation associated with diseased states.

Ca2+/Calmodulin Inhibition and Phospholipase C-Linked Ca2+ Signaling in Clonalβ -Cells1

Neurotransmitters and hormones, such as arginine vasopressin (AVP) and bombesin, evoke frequency-modulated repetitive Ca2+ transients in insulin-secreting HIT-T15 cells by binding to receptors linked to phospholipase C (PLC). The role of calmodulin (CaM)-dependent mechanisms in the generation of PLC-linked Ca2+ transients was investigated by use of the naphthalenesulfonamide CaM antagonists W-7 and W-13 and their dechlorinated control analogs W-5 and W-12. W-7 (10–30μ m) and W-13 (30–100 μm), but not W-5 (100μ m) and W-12 (300 μm), reversibly inhibited the AVP- and bombesin-induced Ca2+ transients. As the generation of PLC-linked Ca2+ transients requires mobilization of internal Ca2+ and Ca2+ influx through voltage-sensitive (VSCC) and -insensitive (VICC) Ca2+ channels, the effects of the W compounds on these processes were further investigated. First, W-7 dose dependently diminished K+ (45 mm)-induced Ca2+ signals (IC50, ∼25 μm), and W-13 (100μ m) reduced the K+ (45 mm)-induced [Ca2+]i rise by about 40–6...

Mechanisms of cellular information processing

Living cells in multicellular organisms are in simultaneous contact with many regulatory factors such as hormones or neurotransmitters. Many of these factors vary with time in their local concentrations, owing to pulsatile release or production. Therefore, complex patterns of signaling factors act on each living cell in vivo, stimulating or inhibiting second-messenger pathways with potentially complex dynamics. These intracellular pathways do not operate independently but are extensively interconnected, creating complex networks and patterns of intracellular signals that combine to determine the cells response. The potential significance of cross-signaling between second-messenger pathways and of dynamic stimulation of receptors for cellular information processing in physiology and pathophysiology are discussed.