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This paper thoroughly discusses the electric activities generated by ion communication between cells and their surrounding environment. Specifically, it focuses on the transients of firing activities of a four-dimensional pituitary model that evolves on three disparate timescales. To examine the impact of inward rectifying K + current and calcium concentration on the firing activities, a bifurcation analysis is conducted, categorizing three primary behaviors: resting, tonic spiking, and bursting. Each behavior is validated through their respective time courses, with the pituitary cells showing higher secretion rates of hormones and neurotransmitters during bursting than spiking. The geometric singular perturbed theory is applied to reveal hidden geometric features and the transient mechanisms associated with bursting, particularly mixed-mode oscillations (MMOs). Singular orbit construction performed in two-timescale separation with different viewpoints offers clarity on the underlying dynamic mechanisms. Canard-induced MMOs are observed in the context of 1 fast/3 slow and 2 fast/2 slow separations, facilitated by the presence of folded saddle-node and folded node, respectively. Additionally, the fast–slow analysis of the 3 fast/1 slow subsystem, which treats calcium concentration c as a parameter, in conjunction with the singular orbit constructions, effectively illustrates the system's complex dynamics. Furthermore, the information obtained in 1 fast/3 slow and 3 fast/1 slow discussions is interplayed in the context of three-timescale separation. The singular orbits identified within three-timescale framework offer a supplemental perspective to the delicate firing patterns observed in two-timescale analysis, enriching the overall understanding of the transient and long-term firing behaviors of the pituitary cells. This study presents valuable insights into the firing features in pituitary cells from the perspectives of dynamic systems. The singular perturbation analysis provides useful viewpoints for accessing firing patterns in multi-timescale systems. [ABSTRACT FROM AUTHOR]

Abstract Pituitary neuroendocrine tumours (PitNETs) are neoplasms of the pituitary that overproduce hormones or cause unspecific symptoms due to mass effect. Growth hormone overproducing GH-producing PitNETs cause acromegaly leading to connective tissue, metabolic or oncologic disorders. The medical treatment of acromegaly is somatostatin analogues (SSA) in specific cases combined with dopamine agonists (DA), but almost half of patients display partial or full SSA resistance and potential causes of this are unknown. In this study we investigated transcriptomic landscape of GH-producing PitNETs on several levels and functional models—tumour tissue of patients with and without SSA preoperative treatment, tumour derived pituispheres and GH3 cell line incubated with SSA to study effect of medication on gene expression. MGI sequencing platform was used to sequence total RNA from PitNET tissue, pituispheres, mesenchymal stromal stem-like cells (MSC), and GH3 cell cultures, and data were analysed with Salmon—DeSeq2 pipeline. We observed that the GH-producing PitNETs have distinct changes in growth hormone related pathways related to its functional status alongside inner cell signalling, ion transport, cell adhesion and extracellular matrix characteristic patterns. In pituispheres model, treatment regimens (octreotide and cabergoline) affect specific cell proliferation (MKI67) and core functionality pathways (RYR2, COL8A2, HLA-G, ARFGAP1, TGFBR2). In GH3 cells we observed that medication did not have transcriptomic effects similar to preoperative treatment in PitNET tissue or pituisphere model. This study highlights the importance of correct model system selection for cell transcriptomic profiling and data interpretation that could be achieved in future by incorporating NGS methods and detailed cell omics profiling in PitNET model research.

Pituitary neuroendocrine tumours (PitNETs) are neoplasms of the pituitary that overproduce hormones or cause unspecific symptoms due to mass effect. Growth hormone overproducing GH-producing PitNETs cause acromegaly leading to connective tissue, metabolic or oncologic disorders. The medical treatment of acromegaly is somatostatin analogues (SSA) in specific cases combined with dopamine agonists (DA), but almost half of patients display partial or full SSA resistance and potential causes of this are unknown. In this study we investigated transcriptomic landscape of GH-producing PitNETs on several levels and functional models—tumour tissue of patients with and without SSA preoperative treatment, tumour derived pituispheres and GH3 cell line incubated with SSA to study effect of medication on gene expression. MGI sequencing platform was used to sequence total RNA from PitNET tissue, pituispheres, mesenchymal stromal stem-like cells (MSC), and GH3 cell cultures, and data were analysed with Salmon—DeSeq2 pipeline. We observed that the GH-producing PitNETs have distinct changes in growth hormone related pathways related to its functional status alongside inner cell signalling, ion transport, cell adhesion and extracellular matrix characteristic patterns. In pituispheres model, treatment regimens (octreotide and cabergoline) affect specific cell proliferation (MKI67) and core functionality pathways (RYR2, COL8A2, HLA-G, ARFGAP1, TGFBR2). In GH3 cells we observed that medication did not have transcriptomic effects similar to preoperative treatment in PitNET tissue or pituisphere model. This study highlights the importance of correct model system selection for cell transcriptomic profiling and data interpretation that could be achieved in future by incorporating NGS methods and detailed cell omics profiling in PitNET model research. [ABSTRACT FROM AUTHOR]

Bursting is an intrinsically electrical activity in excitable cells such as endocrine cells and many types of neurons. Our purpose is to recognize the pituitary model from a new perspective and provide guidance for its further improvement by exploring the mechanism of bursting generation and its dynamic behavior. The technique of slow-fast dynamics analysis is very helpful when analyzing two subsystems that vary significantly in time scale. Based on the original model, A-type potassium channels and BK-type potassium channels are added simultaneously to the system. And its dynamical property differs from merely adding a fast potassium ion channel (A-type or BK-type). We acquire a deeper understanding for the novel bursting pattern (pseudo-plateau) from discussing the original system to considering bifurcation analysis to the whole system. We mainly explore the existence of mixed-mode oscillations (MMOs) in the improved pituitary model and its bifurcation behaviors via using geometric singular perturbation theory and slow-fast dynamics analysis, respectively. The result we obtained is very helpful in explaining mathematical mechanisms and improving the pituitary model. [ABSTRACT FROM AUTHOR]

This study in normal male subjects further investigates the effects of dopaminergic-antidopaminergic interactions as manifested by the prolactin response to dopamine and neuroleptic drugs. Incremental doses of dopamine hydrochloride (4 μg/min, 15 μg/min, 60 μg/min, 300 μg/min) were infused fused at a constant rate over 90-120 min after a fixed dose of a neuroleptic drug (sufficient for about half of the maximal prolactin response) had been given IV. A dose of dopamine in the order of 15-60 μg/min appeared to match the 'los' of endogenous dopaminergic inhibition due to the antidopaminergic effect of the neuroleptic drug. The lactotrophic cells of the pituitary gland are suggested to serve as a model in man for the study of some basic neurohormonal mechanisms. [ABSTRACT FROM AUTHOR]