Gap junction-mediated intercellular communication in the adrenal medulla: an additional ingredient of stimulus-secretion coupling regulation.

The traditional understanding of stimulus-secretion coupling in adrenal neuroendocrine chromaffin cells states that catecholamines are released upon trans-synaptic sympathetic stimulation mediated by acetylcholine released from the splanchnic nerve terminals. Although this statement remains largely true, it deserves to be tempered. In addition to its neurogenic control, catecholamine secretion also depends on a local gap junction-mediated communication between chromaffin cells. We review here the insights gained since the first description of gap junctions in the adrenal medullary tissue. Adrenal stimulus-secretion coupling now appears far more intricate than was previously envisioned and its deciphering represents a challenge for neurobiologists engaged in the study of the regulation of neuroendocrine secretion. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.

Functional characterization of alpha9-containing cholinergic nicotinic receptors in the rat adrenal medulla: implication in stress-induced functional plasticity.

An increase in circulating adrenal catecholamine levels constitutes one of the mechanisms whereby organisms cope with stress. Accordingly, stimulus-secretion coupling within the stressed adrenal medullary tissue undergoes persistent remodeling. In particular, cholinergic synaptic neurotransmission between splanchnic nerve terminals and chromaffin cells is upregulated in stressed rats. Since synaptic transmission is mainly supported by activation of postsynaptic neuronal acetylcholine nicotinic receptors (nAChRs), we focused our study on the role of alpha9-containing nAChRs, which have been recently described in chromaffin cells. Taking advantage of their specific blockade by the alpha-conotoxin RgIA (alpha-RgIA), we unveil novel functional roles for these receptors in the stimulus-secretion coupling of the medulla. First, we show that in rat acute adrenal slices, alpha9-containing nAChRs codistribute with synaptophysin and significantly contribute to EPSCs. Second, we show that these receptors are involved in the tonic inhibitory control exerted by cholinergic activity on gap junctional coupling between chromaffin cells, as evidenced by an increased Lucifer yellow diffusion within the medulla in alpha-RgIA-treated slices. Third, we unexpectedly found that alpha9-containing nAChRs dominantly (>70%) contribute to acetylcholine-induced current in cold-stressed rats, whereas alpha3 nAChRs are the main contributing channels in unstressed animals. Consistently, expression levels of alpha9 nAChR transcript and protein are overexpressed in cold-stressed rats. As a functional relevance, we propose that upregulation of alpha9-containing nAChR channels and ensuing dominant contribution in cholinergic signaling may be one of the mechanisms whereby adrenal medullary tissue appropriately adapts to increased splanchnic nerve electrical discharges occurring in stressful situations.

Functional remodeling of gap junction-mediated electrical communication between adrenal chromaffin cells in stressed rats.

An increase in circulating catecholamine levels represents one of the mechanisms whereby organisms cope with stress. In the periphery, catecholamines mainly originate from the sympathoadrenal system. As we reported, in addition to the central control through cholinergic innervation, a local gap junction-delineated route between adrenal chromaffin cells contributes to catecholamine exocytosis. Here, we investigated whether this intercellular communication is modified when the hormonal demand is increased as observed during cold stress. Our results show that in cold exposed rats, gap-junctional communication undergoes a functional plasticity, as evidenced by an increased number of dye-coupled cells. Of a physiological interest is that this upregulation of gap-junctional coupling results in the appearance of a robust electrical coupling between chromaffin cells that allows the transmission of action potentials between coupled cells. This enhancement of gap-junctional communication parallels an increase in expression levels of connexin36 (Cx36) and connexin43 (Cx43) proteins. Both transcriptional and posttranslational mechanisms are involved because Cx36 transcripts are increased in stressed rats and the expression of the scaffolding protein zonula occludens-1, known to interact with both Cx36 and Cx43, is also upregulated. Consistent with an upregulated coupling extent in stressed rats, the cytosolic Ca(2+) concentration rises triggered in a single cell by an iontophoretic application of nicotine occur simultaneously in several neighboring cells. These results describe for the first time a functional plasticity of junctional coupling between adult chromaffin cells that should be crucial for adaptation to stress or sensitization to subsequent stressors.

Revisiting the stimulus-secretion coupling in the adrenal medulla: role of gap junction-mediated intercellular communication.

The current view of stimulation-secretion coupling in adrenal neuroendocrine chromaffin cells holds that catecholamines are released upon transsynaptic sympathetic stimulation mediated by acetylcholine released from the splanchnic nerve terminals. However, this traditional vertical scheme would merit to be revisited in the light of recent data. Although electrical discharges invading the splanchnic nerve endings are the major physiological stimulus to trigger catecholamine release in vivo, growing evidence indicates that intercellular chromaffin cell communication mediated by gap junctions represents an additional route by which biological signals (electrical activity, changes in intracellular Ca(2+) concentration,...) propagate between adjacent cells and trigger subsequent catecholamine exocytosis. Accordingly, it has been proposed that gap junctional communication efficiently helps synapses to lead chromaffin cell function and, in particular, hormone secretion. The experimental clues supporting this hypothesis are presented and discussed with regards to both interaction with the excitatory cholinergic synaptic transmission and physiopathology of the adrenal medulla.

Regulator of G protein signaling-4 controls fatty acid and glucose homeostasis.

Circulating free fatty acids are a reflection of the balance between lipogenesis and lipolysis that takes place mainly in adipose tissue. We found that mice deficient for regulator of G protein signaling (RGS)-4 have increased circulating catecholamines, and increased free fatty acids. Consequently, RGS4-/- mice have increased concentration of circulating free fatty acids; abnormally accumulate fatty acids in liver, resulting in liver steatosis; and show a higher degree of glucose intolerance and decreased insulin secretion in pancreas. We show in this study that RGS4 controls adipose tissue lipolysis through regulation of the secretion of catecholamines by adrenal glands. RGS4 controls the balance between adipose tissue lipolysis and lipogenesis, secondary to its role in the regulation of catecholamine secretion by adrenal glands. RGS4 therefore could be a good target for the treatment of metabolic diseases.

Insulin-like growth factor-1 inhibits adult supraoptic neurons via complementary modulation of mechanoreceptors and glycine receptors.

In the CNS, insulin-like growth factor-1 (IGF-1) is mainly known for its trophic effect both during development and in adulthood. Here, we show than in adult rat supraoptic nucleus (SON), IGF-1 receptor immunoreactivity is present in neurons, whereas IGF-1 immunoreactivity is found principally in astrocytes and more moderately in neurons. In vivo application of IGF-1 within the SON acutely inhibits the activity of both vasopressin and oxytocin neurons, the two populations of SON neuroendocrine cells. Recordings of acutely isolated SON neurons showed that this inhibition occurs through two rapid and reversible mechanisms, both involving the neuronal IGF-1 receptor but different intracellular messengers. IGF-1 inhibits Gd3+-sensitive and osmosensitive mechanoreceptor cation current via phosphatidylinositol-3 (PI3) kinase activation. IGF-1 also potentiates taurine-activated glycine receptor (GlyR) Cl- currents by increasing the agonist sensitivity through a extremely rapid (within a second) PI3 kinase-independent mechanism. Both mechanoreceptor channels and GlyR, which form the excitatory and inhibitory components of SON neuron osmosensitivity, are active at rest, and their respective inhibition and potentiation will both be inhibitory, leading to strong decrease in neuronal activity. It will be of interest to determine whether IGF-1 is released by neurons, thus participating in an inhibitory autocontrol, or astrocytes, then joining the growing family of glia-to-neuron transmitters that modulate neuronal and synaptic activity. Through the opposite and complementary acute regulation of mechanoreceptors and GlyR, IGF-1 appears as a new important neuromodulator in the adult CNS, participating in the complex integration of neural messages that regulates the level of neuronal excitability.

Stress-induced intercellular communication remodeling in the rat adrenal medulla.

To understand the mechanisms by which a prolonged exposure to stress enhances catecholamine secretion, we examined the effects of 5-day cold exposure on cell-cell communication pathways in the rat adrenal medulla. Upon stress, the neurosecretory tissue undergoes dramatic morphofunctional changes resulting in increased chromaffin cell excitability, upregulation of both chemical transmission at the splanchnic nerve terminal-chromaffin cell synapses and spreading of gap junction-permeant Lucifer yellow between cells. All these changes converge to improve the stimulus-secretion coupling efficiency within the adrenal medulla and subsequently to adapt catecholamine release to a sustained organism demand.