Signal Transduction in Pituitary Functions

Abstract

Signal transduction plays a crucial role in the intricate functioning of the pituitary gland. Dopamine receptor type 2 (DRD2) signaling is representative. The actin-binding protein filamin A (FLNA) is essential for the expression and signaling of dopamine receptor type 2 (DRD2) in GH- and PRL-secreting pituitary tumors (PitNETs). FLNA acts, facilitating DRD2 signal transduction and influencing tumor responsiveness to dopaminergic drugs and somatostatin receptor ligands. Remarkably, when FLNA is phosphorylated at Ser2152 (P-FLNA), its role transitions from being a scaffold that facilitates SSTR2 signal transduction to becoming a signal termination protein that impairs SSTR2’s antitumoral effects in GH-secreting PitNETs. Activation of the cAMP pathway and stimulation of DRD2 agonists impact P-FLNA levels. Overexpression of a phosphomimetic (S2152D) FLNA mutant prevents DRD2’s antiproliferative effects, emphasizing the role of P-FLNA in DRD2 signaling. These include the phosphorylation of Janus Kinase (Jak) 2 and Signal Transduction and Activator of Transcription (STAT) 5. Once phosphorylated, these proteins modulate the activity of specific genes. For instance, they enhance the expression of tyrosine hydroxylase, which stimulates dopamine production, and activate the beta-casein gene, promoting milk protein synthesis. In lower vertebrates, the pituitary gland exhibits signal transduction mechanisms related to the glucagon-like peptide-1 (GLP-1) system.

1. Introduction

Hormones play a vital role in coordinating various processes within an organism. As per the definition of hormones: Hormones are biochemical substances produced and released by cells or glands in one part of the body. These messengers travel through the bloodstream to target cells and organs elsewhere in the body, influencing their activity and function. Remarkably, only a small amount of pituitary hormone is required to alter cell metabolism. Essentially, its transport signals are based on orchestra of responses in the body. Generally pituitary hormones are water-soluble and cannot diffuse through the plasma membrane. Their receptors are located outside the cell membrane. Meanwhile, non-polar hormones are lipid-soluble and can diffuse through the membrane [1]. Their receptors are inside the cell. For example, steroid hormones directly control transcription viabinding to intracellular receptors. Pituitary hormones initiate a cascade of events through signal transduction pathways [1, 2, 3]. The effect of the pathway induces a single stimulation to activate the large number of molecules, causing changes from subtle to pathological [4].

In this chapter, we focus on signal transduction in pituitary functions.

2. Discussion

2.1 Dopamine receptor type 2 signaling

Dopamine D2 receptors (DRD2) play a significant role in the pituitary gland [5]. DRD2 is a type of dopamine receptor found in the pituitary gland. It is involved in regulating the secretion of various hormones, including prolactin. Prolactin is a hormone secreted by lactotrophs in the anterior pituitary gland [6]. Elevated prolactin levels are associated with increased food intake. In some cases, such as in global dopamine D2 receptor knockout mice, food intake is not increased despite high prolactin levels. To study the specific role of elevated prolactin levels without influence of central D2 receptors [7], researchers used conditional mutants that selectively lack D2Rs from lactotrophs (lacDrd2KO). LacDrd2KO female mice exhibited chronic hyperprolactinemia, pituitary hyperplasia, and a preserved GH axis [8, 9]. Interestingly, these female mice showed increased food intake and heavier body weights from 5 months onward. Other metabolic changes included increased fat depots, altered adipocyte size, elevated serum triglycerides, and decreased lipolytic enzymes in adipose tissue. Glucose intolerance was also observed in lacDrd2KO female mice, although their response to insulin remained intact [9].

2.2 Filamin A (FLNA) and pituitary tumor

Corticotrophinomas are ACTH-secreting pituitary tumors associated with Cushing’s disease (CD). CD results from excessive cortisol production, leading to metabolic complications. Pituitary surgery is the primary treatment, but medical options like cabergoline (CAB) are also used. FLNA, an actin-binding protein, is crucial for DRD2 and somatostatin receptor 2 (SST2) expression in pituitary tumors [10]. Also, in prolactinomas, FLNA correlates with DRD2 expression. However, in corticotrophinomas, there are limited studies on DRD2 expression and no data on FLNA [11]. Researchers evaluated DRD2 and FLNA expression in 23 corticotrophinoma samples [12]. DRD2 was present in 89% of cases but did not correlate with FLNA expression. CAB treatment is not related to DRD2 or FLNA expression and is unrelated to most tumor features, only sinus invasion for the sphenoid. In corticotrophinoma, the expression of DRD2 does not associate with FLNA or CAB treatment. However, this FLNA may play a role in tumor invasiveness in several tumors [12, 13, 14]. FLNA and DRD2 interfaces in corticotrophinoma remain intriguing.

2.3 Prolactin (PRL) regulation

Prolactin (PRL) is a versatile polypeptide hormone primarily secreted by lactotrophic cells in the anterior pituitary gland of vertebrates. It plays a crucial role in lactation and reproduction, as well as having diverse effects related to growth, development, metabolism, immunoregulation, and protection. The prolactin signaling pathway commences with the interaction between prolactin and its receptor, known as the prolactin receptor (PRLR). This receptor includes the superfamily of class 1 cytokine receptors in diverse tissues [15]. The PRLR has three ligand-binding domains an extracellular, a transmembrane, and an intracellular. Notably, the PRLR has no intrinsic kinase activity and instead transmits signals mediated by kinases with cellular organella [16]. In humans, these constitutive receptors are known. The primary signaling pathway triggered by the interaction between prolactin and its receptor, Prolactin Receptor (PRLR), is the JAK/STAT pathway. Upon binding of prolactin to PRLR, a cascade of events is initiated, leading to the activation of Janus kinases (JAKs) and subsequent phosphorylation of signal transducers and activators of transcription (STATs). These phosphorylated STAT proteins then translocate to the nucleus, modulating gene expression and influencing various cellular processes [17]. This leads to the phosphorylation of multiple tyrosine on the receptor, which can influence the binding of a downstream signaling cascade such as STAT protein [18, 19, 20]. These phosphorylated proteins act on relevant genes encoding tyrosine hydroxylase and beta-casein genes.

2.4 Glucagon-like peptide-1 (GLP-1) signal

GLP-1, or glucagon-like peptide-1, is a peptide hormone. It originates from the specific processing of the proglucagon peptide after undergoing tissue-specific posttranslational modifications. GLP-1 is synthesized in two primary locations that are intestinal endocrine L-cells and nucleus of the solitary tract in the brainstem. GLP-1 has a crucial physiological role in glucose homeostasis and satiety regulation. It stimulates insulin secretion from pancreatic beta cells, promoting glucose uptake by tissues. GLP-1 also inhibits glucagon release, reducing blood sugar levels. Additionally, it slows gastric emptying, contributing to feelings of fullness after meals. While GLP-1 affects the hypothalamus, its direct impact on pituitary luteinizing hormone (LH) release is less pronounced [21, 22]. Pituitary GLP-1 receptor expression is lower compared to hypothalamic levels. Distinct proglucagons and their functional cognate receptors are present in the pituitary gland [23].

2.5 Pit-1 in pituitary tumor growth

The anterior pituitary-specific transcription factor Pit-1, also referred to as PitNETs, was initially cloned due to its role as a transactivator for the growth hormone (GH), prolactin (PRL), and thyroid-stimulating beta-subunit (TSHb) genes [24]. Pit-1 expression during mouse embryogenesis disclosed that initiation of its expression correlates with Pit-1. In particular, the absence of these three cell pituitary glands of Pit-1 defective animals shows its key regulator of anterior pituitary development [25]. Pit-1, a transcription factor essential for both cell phenotype and proliferation, has drawn attention regarding its potential involvement in pituitary tumor growth. Numerous researchers have documented Pit-1 gene expression within human pituitary adenomas. However, these studies do not universally agree on the association between pituitary tumorigenesis and significant alterations in Pit-1 expression. Again, Pit-1 transcripts—identical in size and sequence to those observed in normal pituitary tissue—have been identified in pituitary adenomas secreting growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH). In addition, expression of the Pit-1gene colocalized with the protein [26]. A recent study indicates that Pit-1 is a type III sodium-phosphate cotransporter that plays a crucial role in the intracellular transport of inorganic phosphate (Pi) [27]. It is widely expressed and involved in cellular Pit-1 homeostasis [28]. However, many aspects of its function are still unclear. Researchers have discovered that signals triggered by extracellular inorganic phosphate and the phosphate-regulating hormone FGF23 share downstream cascades involving Pit-1 and FGF receptors [29]. These cascades are essential for maintaining phosphate balance in the body.

3. Conclusion

The pituitary’s actions are guided by intricate signaling pathways. Signals emanate from both the ventral diencephalon/infundibulum and Rathke’s pouch. These cues orchestrate hormonal release, growth, and feedback loops.