The molecular function of adrenal chromaffin granules: Established facts and unresolved topics

The adrenal glands are key components of the mammalian endocrine system, helping maintain physiological homeostasis and the coordinated response to stress. Each adrenal gland has two morphologically and functionally distinct regions, the outer cortex and inner medulla. The cortex is organized into three concentric zones which secrete steroid hormones, including aldosterone and cortisol. Neural crest-derived chromaffin cells in the medulla are innervated by preganglionic sympathetic neurons and secrete catecholamines (epinephrine, norepinephrine) and neuropeptides into the bloodstream, thereby functioning as the neuroendocrine arm of the sympathetic nervous system. In this article we review serotonin (5-HT) and the serotonin transporter (SERT; SLC6A4) in the adrenal gland. In the adrenal cortex, 5-HT, primarily sourced from resident mast cells, acts as a paracrine signal to stimulate aldosterone and cortisol secretion through 5-HT₄/5-HT₇ receptors. Medullary chromaffin cells contain a small amount of 5-HT due to SERT-mediated uptake and express 5-HT_1A receptors which inhibit secretion. The atypical mechanism of the 5-HT_1A receptors and interaction with SERT fine tune this autocrine pathway to control stress-evoked catecholamine secretion. Receptor-independent signaling by SERT/intracellular 5-HT modulates the amount and kinetics of transmitter release from single vesicle fusion events. SERT might also influence stress-evoked upregulation of tyrosine hydroxylase transcription. Transient signaling via 5-HT₃ receptors during embryonic development can limit the number of chromaffin cells found in the mature adrenal gland. Together, this emerging evidence suggests that the adrenal medulla is a peripheral hub for serotonergic control of the sympathoadrenal stress response.

Exocytosis operates through two distinct modes. Full-fusion leads to rapid expulsion of the entire content of a vesicle; kiss-and-run leads to slow and partial expulsion. These two modes have important biological consequences for endocrine regulation and synaptic transmission. Amperometry recordings of catecholamine release from chromaffin cells reveal single-vesicle fusion events corresponding to both of these modes, but classification is often difficult. This study introduces a new method of analyzing amperometry data to improve this classification. The ratio of the average amplitude to the peak amplitude differs between full-fusion and kiss-and-run, and the probability distribution of this ratio is well fitted by a double-Gaussian. Kiss-and-run events identified by this method have fusion pores with kinetic properties different from pores associated with full-fusion. They have slower transition rates and lifetime distributions indicative of irreversible transitions. The total-charge of an amperometric spike is expected to scale with vesicle volume during a full-fusion event. The cube root of this quantity should therefore scale with diameter, but the distribution of this quantity differs from the distribution of vesicle diameter seen in the electron microscope. Fusion pore lifetimes associated with full-fusion depend on vesicle size, and this makes the choice of mode size dependent. The fusion pore thus bifurcates after opening, and vesicle size influences this choice. The secretory vesicle protein synaptophysin influences the size dependence of fusion pore lifetime and the choice of release mode. Incorporating vesicle size into an analysis of release mode reconciled the kinetics of fusion pores, as well as the distributions of vesicle diameter and catecholamine content. Thus, the initial fusion pore emerges as a critical focus in endocrine regulation. By modulating the size-dependence of the mode of exocytosis, changes in the molecular makeup of the exocytotic apparatus can impact the shape and size of an amperometric event, and the speed and composition of secretion.

Dioxygen activations constitute one of core issues in copper-dependent metalloenzymes. Upon O₂ activation, copper-dependent metalloenzymes such as particulate methane monooxygenases (pMMOs), lytic polysaccharide monooxygenases (LPMOs) and binuclear copper enzymes PHM and DβM, are able to perform various challenging C–H bond activations. Meanwhile, various copper-oxygen core containing complexes have been synthetized to mimic the active species of metalloenzymes. Dioxygen activation by mononuclear copper active site may generate various copper-oxygen intermediates, including Cu(II)-superoxo, Cu(II)-hydroperoxo, Cu(II)-oxyl as well as the Cu(III)-hydroxide species. Intriguingly, all these species have been invoked as the potential active intermediates for C–H/O–H activations in either biological or synthetic systems. Due to the poor understanding on reactivities of copper-oxygen complex, the nature of active species in both biological and synthetic systems are highly controversial. In this account, we will compare the reactivities of various mononuclear copper-oxygen species between biological systems and the synthetic systems. The present study is expected to provide the consistent understanding on reactivities of various copper-oxygen active species in both biological and synthetic systems.

The evolution of peptidergic signaling systems in the central nervous system serves a distinct and crucial role in brain processes and function. The diversity of physiological peptides and the complexity of their regulation and secretion from the dense core vesicles (DCV) throughout the brain is a topic greatly in need of investigation, though recent years have shed light on cellular and molecular mechanisms that are summarized in this review. Here, we focus on the convergence of peptidergic systems onto the Locus Coeruleus (LC), the sole provider of norepinephrine (NE) to the cortex and hippocampus, via large DCV. As the LC-NE system is one of the first regions of the brain to undergo degeneration in Alzheimer’s Disease (AD), and markers of DCV have consistently been demonstrated to have biomarker potential for AD progression, here we summarize the current literature linking the LC-NE system with DCV dysregulation and Aβ peptides. We also include neuroanatomical data suggesting that the building blocks of senile plaques, Aβ monomers, may be localized to DCV of the LC and noradrenergic axon terminals of the prefrontal cortex. Finally, we explore the putative consequences of chronic stress on Aβ production and the role that DCV may play in LC degeneration. Clinical data of immunological markers of DCV in AD patients are discussed.

The adrenal glands consist of a cortex, which is essential for life, and medulla, which is not. The cortex comprises three zones: the zona glomerulosa, zona fasciculata, and zona reticularis, which secrete mineralocorticoids, glucocorticoids, and sex hormones, respectively. The medulla secretes epinephrine, norepinephrine, dopamine, and opioid peptides. The adrenal gland is one of the endocrine glands most sensitive to chemical toxicity. Degenerative changes in the cortex include vacuolation, cystic degeneration, focal hypertrophy, hyperplasia, and cortical tumors. Proliferative medullary lesions are common in aging rats, with higher incidences in males. In addition to hyperplasia and benign and malignant pheochromocytoma, which are seen most commonly, complex pheochromocytomas, ganglioneuromas, and neuroblastomas are occasionally reported.

VMAT2 is the vesicular monoamine transporter that allows DA, NE, Epi, His, and 5-HT uptake into neurons and endocrine cells. A second isoform, VMAT1, has similar structure and function, but does not recognize histamine as a substrate. VMAT1 is absent from neurons, and its major function appears to be in endocrine cells, that is, enterochromaffin cells, which scavenge 5-HT, but not histamine, from dietary sources. This chapter provides an update on the neuroanatomical distribution of VMAT2 across various mammalian species, including human, primate, pig, rat, and mouse. When necessary, VMAT1 expression is provided as a contrast. The main purpose of this chapter is to allow clinicians, in particular endocrinologists and diagnosing neuroradiologists and neuropathologists, an acquaintanceship with the possibilities for VMAT2 as a target for in vivo imaging, and drug development, based on this updated information.