Belal Marziyeh, Mucha Mariusz, Monteil Arnaud, Winyard Paul G, Pawlak Robert, Walker Jamie J, Tabak Joel, Belle Mino D C
University of Exeter Medical School, Hatherly Labs, Exeter, Devon, UK.
Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
J Physiol. 2025 Jan;603(2):301-317. doi: 10.1113/JP284036. Epub 2024 Dec 2.
The pituitary gland produces and secretes a variety of hormones that are essential to life, such as for the regulation of growth and development, metabolism, reproduction, and the stress response. This is achieved through an intricate signalling interplay between the brain and peripheral feedback signals that shape pituitary cell excitability by regulating the ion channel properties of these cells. In addition, endocrine anterior pituitary cells spontaneously fire action potentials to regulate the intracellular calcium ([Ca]) level, an essential signalling conduit for hormonal secretion. To this end, pituitary cells must regulate their resting membrane potential (RMP) close to the firing threshold, but the molecular identity of the ionic mechanisms responsible for this remains largely unknown. Here, we revealed that the sodium leak channel NALCN, known to modulate neuronal excitability elsewhere in the brain, regulates excitability in the mouse anterior endocrine pituitary cells. Using viral transduction combined with powerful electrophysiology methods and calcium imaging, we show that NALCN forms the major Na leak conductance in these cells, appropriately tuning cellular RMP for sustaining spontaneous firing activity. Genetic depletion of NALCN channel activity drastically hyperpolarised these cells, suppressing their firing and [Ca] oscillations. Remarkably, despite this profound function of NALCN conductance in controlling pituitary cell excitability, it represents a very small fraction of the total cell conductance. Because NALCN responds to hypothalamic hormones, our results also provide a plausible mechanism through which hormonal feedback signals from the brain and body could powerfully affect pituitary activity to influence hormonal function. KEY POINTS: Pituitary hormones are essential to life as they regulate important physiological processes, such as growth and development, metabolism, reproduction and the stress response. Pituitary hormonal secretion relies on the spontaneous electrical activity of pituitary cells and co-ordinated inputs from the brain and periphery. This appropriately regulates intracellular calcium signals in pituitary cells to trigger hormonal release. Using viral transduction in combination with electrophysiology and calcium imaging, we show that the activity of the background leak channel NALCN is a major controlling factor in eliciting spontaneous electrical activity and intracellular calcium signalling in pituitary cells. Remarkably, our results revealed that a minute change in NALCN activity could have a major influence on pituitary cell excitability. Our study provides a plausible mechanism through which the brain and body could intricately control pituitary activity to influence hormonal function.
垂体产生并分泌多种对生命至关重要的激素，例如用于调节生长发育、新陈代谢、生殖以及应激反应。这是通过大脑与外周反馈信号之间复杂的信号相互作用来实现的，这些信号通过调节这些细胞的离子通道特性来塑造垂体细胞的兴奋性。此外，内分泌性垂体前叶细胞会自发产生动作电位，以调节细胞内钙（[Ca]）水平，这是激素分泌的重要信号传导途径。为此，垂体细胞必须将其静息膜电位（RMP）调节至接近放电阈值，但负责此过程的离子机制的分子身份在很大程度上仍不清楚。在这里，我们发现钠漏通道NALCN（已知可调节大脑其他部位的神经元兴奋性）可调节小鼠垂体前叶内分泌细胞的兴奋性。通过病毒转导结合强大的电生理方法和钙成像，我们表明NALCN在这些细胞中形成主要的钠漏电导，适当地调节细胞RMP以维持自发放电活动。NALCN通道活性的基因缺失使这些细胞急剧超极化，抑制了它们的放电和[Ca]振荡。值得注意的是，尽管NALCN电导在控制垂体细胞兴奋性方面具有这种重要功能，但它仅占细胞总电导的很小一部分。由于NALCN对下丘脑激素有反应，我们的结果还提供了一种合理的机制，通过该机制来自大脑和身体的激素反馈信号可以有力地影响垂体活动，从而影响激素功能。要点：垂体激素对生命至关重要，因为它们调节重要的生理过程，如生长发育、新陈代谢、生殖和应激反应。垂体激素分泌依赖于垂体细胞的自发电活动以及大脑和外周的协调输入。这适当地调节垂体细胞内的钙信号以触发激素释放。通过将病毒转导与电生理和钙成像相结合，我们表明背景漏通道NALCN的活性是引发垂体细胞自发电活动和细胞内钙信号传导的主要控制因素。值得注意的是，我们结果表明NALCN活性的微小变化可能对垂体细胞兴奋性产生重大影响。我们的研究提供了一种合理的机制，通过该机制大脑和身体可以复杂地控制垂体活动以影响激素功能。
