Paracrinicity: the story of 30 years of cellular pituitary crosstalk

Abstract

Living organisms represent, in essence, dynamic interactions of high complexity between membrane-separated compartments that cannot exist on their own, but reach behaviour in co-ordination. In multicellular organisms, there must be communication and co-ordination between individual cells and cell groups to achieve appropriate behaviour of the system. Depending on the mode of signal transportation and the target, intercellular communication is neuronal, hormonal, paracrine or juxtacrine. Cell signalling can also be self-targeting or autocrine. Although the notion of paracrine and autocrine signalling was already suggested more than 100 years ago, it is only during the last 30 years that these mechanisms have been characterised. In the anterior pituitary, paracrine communication and autocrine loops that operate during fetal and postnatal development in mammals and lower vertebrates have been shown in all hormonal cell types and in folliculo-stellate cells. More than 100 compounds have been identified that have, or may have, paracrine or autocrine actions. They include the neurotransmitters acetylcholine and gamma-aminobutyric acid, peptides such as vasoactive intestinal peptide, galanin, endothelins, calcitonin, neuromedin B and melanocortins, growth factors of the epidermal growth factor, fibroblast growth factor, nerve growth factor and transforming growth factor-beta families, cytokines, tissue factors such as annexin-1 and follistatin, hormones, nitric oxide, purines, retinoids and fatty acid derivatives. In addition, connective tissue cells, endothelial cells and vascular pericytes may influence paracrinicity by delivering growth factors, cytokines, heparan sulphate proteoglycans and proteases. Basement membranes may influence paracrine signalling through the binding of signalling molecules to heparan sulphate proteoglycans. Paracrine/autocrine actions are highly context-dependent. They are turned on/off when hormonal outputs need to be adapted to changing demands of the organism, such as during reproduction, stress, inflammation, starvation and circadian rhythms. Specificity and selectivity in autocrine/paracrine interactions may rely on microanatomical specialisations, functional compartmentalisation in receptor-ligand distribution and the non-equilibrium dynamics of the receptor-ligand interactions in the loops.

Fig. 1

Schematic representation of the paracrine systems acting between gonadotrophs and lactotrophs. Full lines indicate pathways for which experimental criteria for paracrine action have been largely met. Interrupted lines are hypothetical interactions proposed on the basis of the presence of the indicated factors in the cell and their pharmacological effects on the other cell. →, Stimulatory effect; ⊥, inhibitory effect; Cl-PRL, cleaved prolactin; αGSU, glycoprotein hormone α-subunit; FSH, follicle-stimulating hormone; GnRH, gonadotophin-releasing hormone; LH, luteinising hormone; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase-activating peptide; POMC, pro-opiomelanocortin; PRL, prolactin; TGF, transforming growth factor.

Fig. 2

Schematic representation of the putative paracrine systems acting between gonadotrophs and somatotrophs. Full lines indicate pathways for which experimental criteria for paracrine action have been largely met. Interrupted lines are hypothetical interactions proposed on the basis of the presence of the indicated factors in the cell and their pharmacological effects on the other cell. →, Stimulatory effect; ⊥, inhibitory effect; CGRP, calcitonin gene-related peptide; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone-releasing hormone; LH, luteinising hormone; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase-activating peptide; TGF, transforming growth factor; TRH, thyroid-releasing hormone.

Fig. 3

Schematic representation of paracrine systems acting between gonadotrophs and corticotrophs. Full lines indicate pathways for which experimental criteria for paracrine action have been largely met. Interrupted lines are hypothetical interactions proposed on the basis of the presence of the indicated factors in the cell and their pharmacological effects on the other cell. →, Stimulatory effect; ⊥, inhibitory effect; ACTH, adrenocorticotrophic hormone; ANP, atrial natriuretic peptide; AVP, arginine-vasopressin; CART, cocaine and amphetamine-regulated transcript; CGRP, calcitonin gene-related peptide; CNP, C-type natriuretic peptide; CRH, corticotrophin-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinising hormone; NMU, neuromedin U; POMC, pro-opiomelanocortin.

Fig. 4

Schematic representation of the autocrine loops acting in lactotrophs. Full lines indicate pathways for which experimental criteria for autocrine action have been largely met. Interrupted lines are hypothetical interactions proposed on the basis of the presence of the indicated factors in the lactotroph and their pharmacological effects on the same cell. →, Stimulatory effect; ⊥, inhibitory effect; ET, endothelin; FGF, fibroblast growth factor; IGF, insulin-like growth factor; NGF, nerve growth factor; PRL, prolactin; TGF, transforming growth factor; VIP, vasoactive intestinal peptide.

Fig. 5

Schematic representation of autocrine loops acting in somatotrophs. Full lines indicate pathways for which experimental criteria for autocrine action have been largely met. Interrupted lines are hypothetical interactions proposed on the basis of the presence of the indicated factors in the somatotroph and their pharmacological effects on the same cell. →, Stimulatory effect; ⊥, inhibitory effect; ET, endothelin; GH, growth hormone; GHRH, growth hormone-releasing hormone; NPY, neuropeptide Y; TGF, transforming growth factor; TRH, thyroid-releasing hormone; VIP, vasoactive intestinal peptide.

Fig. 6

Schematic representation of autocrine loops acting in gonadotrophs. Full lines indicate pathways for which experimental criteria for autocrine action have been largely met. Interrupted lines are hypothetical interactions proposed on the basis of the presence of the indicated factors in the gonadotroph and their pharmacological effects on the same cell. →, Stimulatory effect; ⊥, inhibitory effect; Act-R, activin receptor; CNP, C-type natriuretic peptide; FS, folliculo-stellate; FSH, follicle-stimulating hormone; GnRH, gonadotophin-releasing hormone; IL, interleukin; iNOS, inducible nitric oxide synthase; LH, luteinising hormone; LPS, lipopolysaccharide; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; PACAP, pituitary adenylate cyclase-activating peptide.

Fig. 7

Tissue architecture of the anterior pituitary showing the epithelial cell cords with hormonal cells and folliculo-stellate (FS) cells, the capillaries (C) with fenestrated endothelial cells (EC) and connective tissue (CT). The cell cords are a cluster of endocrine cells surrounding an aggregate of FS cells that make a follicle (F). FS cells also make a meshwork between the hormonal cells, making junctions among each other (thick lines) and extending foot processes (f) ending on the basal membrane (BM) in the periphery of the cord. The cords are surrounded by BM, which may have extensions between some cells. A second BM surrounds the capillary vessels and between these two some connective tissue resides. Small and larger lacunae are present between hormonal cells. Paracrine substances may circulate from cell-to-cell but also could be released in these lacunae and reach more remote places. FS cells make gap junctions mostly among each other, but occasionally also with some hormonal cells. Hormonal cells can make interdigitations with FS cells (small arrows) to favour cell-to-cell communication. Adapted from Vila-Porcile (664).

Fig. 8

Schematic representation of the paracrine loops thought to act between folliculo-stellate (FS) cells and hormonal cell types and of autocrine loops in FS cells. Interrupted lines indicate hypothetical interactions proposed on the basis of the presence of the indicated factors in the cell and their pharmacological effects on the same cell. →, Stimulatory effect; ⊥, inhibitory effect; ABC-A1, ATP binding cassette A1 transporter; ACTH, adrenocorticotrophic hormone; CRH, corticotrophin-releasing hormone; GC, guanylate cyclase; FGF, fibroblast growth factor; FS, folliculo-stellate; GH, growth hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotophin-releasing hormone; IL, interleukin; iNOS, inducible nitric oxide synthase; LH, luteinising hormone; LIF, leukaemia-inhibitory factor; LPS, lipopolysaccharide; MIF, migration inhibitory protein; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; PACAP, pituitary adenylate cyclase-activating peptide; POMC, pro-opiomelanocortin; PRL, prolactin; TGF, transforming growth factor; TRH, thyroid-releasing hormone; VEGF, vascular endothelial growth factor; VIP, vasoactive intestinal peptide.

Fig. 9

Schematic representation of cholinergic and GABA-ergic paracrine loops thought to act between hormonal cell types and their relationship with nonhormonal cells and adrenergic signals. →, Stimulatory effect; ⊥, inhibitory effect; A, B, C, GABA_A, GABA_B and GABA_C receptor subtypes, respectively; 2, 2-adrenergic receptor; 1, 1-adrenergic receptor; ?, unknown factor from unknown small cells, that potentiates the growth hormone response to epinephrine. ACTH, adrenocorticotrophic hormone; CRH, corticotrophin-releasing hormone; FS, folliculo-stellate; GH, growth hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotophin-releasing hormone; LH, luteinising hormone; PRL, prolactin; TRH, thyroid-releasing hormone; TSH, thyroid-stimulating hormone.