T-type Calcium Channels during Neuroendocrine Differentiation

cells produce and release (neuro) hormones, neuropeptides or monoamines in the extracellular milieu using a regulated pathway in response to a specific stimulus. The NE system includes specific organs, where cells are organized into secreting tissues (adrenals or pituitary for instance) and a diffuse system, where endocrine cells are scattered in an apparently disorganized pattern among non-secretory cells. The observation of dispersed NE cells throughout the body derives from the seminal works of Heidenhain, Kulchitsky, Masson and Hamperl in the late 19th century and the early 20th century. Their studies demonstrated, from the ability of cells to be stained by silver salts (argent affinity or argyrophily), the existence of dispersed hormone-secreting cells in non-endocrine tissues.

Using histological techniques,Feyrter and Froelich identified the existence of many clear cells (Hellen Zellen) throughout the body and noticeably in the gut, leading to the concept of DNES. Miscellaneous sites were also identified in the prostate, where they are dispersed in the normal epithelium, representing only about 0.5 to 2 % of the total cell population. Anton Pearse then defined NE cells as cells sharing the common ability to uptake and decarboxylate amine precursors, to convert these precursors into biogenic amines and neurotransmitters. From this property, Pearse coined the term, APUD system (Amine Precursor Uptake and Decarboxylation). NE cells were all initially thought to originate only from neuroectoderm (neural crest) and were thus also termed para neurons. However, subsequent studies showed that some of them did not derive from the neural crest. These include pancreatic endocrine cells or gastrointestinal enterochromaffin cells, which originate from endodermal tissue.

NE cells are usually characterized by various functional, morphological and molecular features (for a review see. A NE cell is characterized in electron microscopy by the presence of electrodense secretory granules containing peptidergic and aminergic neurohormones. NE cells possess the capability to rapidly release their neurohormones or neurotransmitters in response to specific stimuli, such as other hormones. In this context, the acquisition of cell excitability, characterized by action potentials and voltage-dependent ion channels, is an important step towards the acquisition of a regulated secretory pathway. Morphologically, the acquisition of a NE phenotype is usually accompanied by the lengthening of neuritic extensions. NE cells therefore share many features with neurons, but do not have specialized nerve terminals or axons. From a molecular point of view, NE cells express specific proteins that may also be expressed by neurons or even by non-neuronal cells. Among these NE markers are the members of the granin family, chromogranin A and B (CgA and CgB), secre-togranin II, III and VII.

These acidic soluble proteins are stored with neuropeptides and neurotransmitters in dense-core vesicles. Other markers of NE differentiation are the enzymes Prohormone Convertases PC1/3 and PC2, which process various protein precursors, including granins, into functional hormones. Like granins and neuropeptides, Prohormone Convertases are stored in dense-core vesicles where they exert their proteolytic activity. These enzymes have therefore been considered as good markers of the NE phenotype or differentiation. These common markers, along with others (neuron-specific enolase (NSE), synaptophysin, S100), are used in pathology to identify NE tumours.