Pituitary adenylate cyclase-activating peptide enhances electrical coupling in the mouse adrenal medulla

Abstract

Hill J, Lee SK, Samasilp P, Smith C. Pituitary adenylate cyclaseactivating peptide enhances electrical coupling in the mouse adrenal medulla. Am J Physiol Cell Physiol 303: C257-C266, 2012. First published May 16, 2012; doi:10.1152/ajpcell.00119.2012.-Neuroendocrine adrenal medullary chromaffin cells receive synaptic excitation through the sympathetic splanchnic nerve to elicit catecholamine release into the circulation. Under basal sympathetic tone, splanchnicreleased acetylcholine evokes chromaffin cells to fire action potentials, leading to synchronous phasic catecholamine release. Under elevated splanchnic firing, experienced under the sympathoadrenal stress response, chromaffin cells undergo desensitization to cholinergic excitation. Yet, stress evokes a persistent and elevated adrenal catecholamine release. This sustained stress-evoked release has been shown to depend on splanchnic release of a peptide transmitter, pituitary adenylate cyclase-activating peptide (PACAP). PACAP stimulates catecholamine release through a PKC-dependent pathway that is mechanistically independent of cholinergic excitation. Moreover, it has also been reported that shorter term phospho-regulation of existing gap junction channels acts to increase junctional conductance. In this study, we test if PACAP-mediated excitation upregulates cell-cell electrical coupling to enhance chromaffin cell excitability. We utilize electrophysiological recordings conducted in adrenal tissue slices to measure the effects of PACAP stimulation on cell coupling. We report that PACAP excitation increases electrical coupling and the spread of electrical excitation between adrenal chromaffin cells. Thus PACAP acts not only as a secretagogue but also evokes an electrical remodeling of the medulla, presumably to adapt to the organism's needs during acute sympathetic stress. acute stress; catecholamine; connexin-43; connexin-36; gap junction ADRENAL MEDULLARY CHROMAFFIN cells are neural crest-derived neurosecretory cells that release catecholamine into the bloodstream (2). Chromaffin cells are innervated by the bifurcating sympathetic splanchnic nerve. Under sympathetic tone, corresponding to the "rest and digest" metabolic state, the splanchnic nerve fires at a modest rate to maintain catecholamine homeostasis. Splanchnic-released acetylcholine binds to nicotinic ionotropic receptors on the chromaffin cell membrane, leading to action potential firing and controlled, phasic catecholamine release (1,7,13,18). Under the acute sympathetic stress response, the splanchnic nerve fires at a heightened rate, leading to rapid and robust cholinergic-evoked catecholamine secretion (25). Yet, the cholinergic pathway rapidly desensitizes (4, 5, 29) while elevated catecholamine secretion persists (44). Pituitary adenylate cyclase-activating peptide (PACAP) is a noncholinergic splanchnic-derived peptide transmitter released selectively during elevated splanchnic firing. PACAP has been identified as the peptide transmitter driving tonic catecholamine secretion after desensi...

Gap junction signalling is a stress-regulated component of adrenal neuroendocrine stimulus-secretion coupling in vivo

“…First, we show here that Cx36 and Cx29 are upregulated after an episode of cold stress, as reported for Cx36 and Cx43 in rat 14 . Second, PACAP, a splanchnic-derived peptide transmitter that is released during elevated nerve firing 10 , enhances gap junction-mediated electrical coupling in the mouse adrenal medulla 57 .…”

Roles of connexins and pannexins in (neuro)endocrine physiology

“…The presence of connexins between chromaffin cells, mainly Cx36 and Cx43, in rodents [12,15,34,35] strongly suggests the involvement of gap junction membrane channels in hormone secretion [36]. In a paper published in the early 2000s, Martin and colleagues [15] described for the first time the presence of functional gap junctional communication between rat chromaffin cells in acute adrenal slices and its role as an additional component of Fig.…”

“…1). The occurrence of gap junctional coupling in the adrenal medulla is highly plastic and depends on various factors (Table 4) [37], including age [38,39], species [30,40], gender [15,34,35], physiological (i.e., stressed/unstressed) state [12,34,41] and splanchnic innervation competence [38,39]. Supporting the role of gap junctions in adrenal medulla endocrine function are data reporting upregulated gap junctional communication between chromaffin cells in response to pharmacological or surgical impairment of splanchnic innervation [38], or in the neonatal adrenal medulla in which the innervation is not yet fully competent [39].…”

“…This is associated with increased expression of both Cx36 and Cx43 [34]. The plasticity of gap junction communication observed in response to stress is not restricted to rat, but is also found in mouse following cold-exposure [12] or application of the pituitary adenylate cyclase-activating peptide (PACAP) [35], a noncholinergic splanchnicderived neurotransmitter selectively released upon high frequency nerve firing [42,43]. Importantly, the recent description of the contribution of gap junctions to catecholamine secretion in vivo [12] significantly advances the knowledge of endocrine/neuroendocrine tissue physiology.…”

“…CC [35] ? CC [35] Guinea pig ± ND [9] Human ? CC [7] ±, sparse; ?, abundant; ND, not determined; CC, chromaffin cells; ST cells, sustentacular cells ?…”