Steroids 69 (2004) 531–536 Estrogen and xenoestrogen actions on endocrine pancreas: from ion channel modulation to activation of nuclear function Angel Nadal ∗ , Ana B. Ropero 1 , Esther Fuentes, Bernat Soria, Cristina Ripoll Institute of Bioengineering, Miguel Hernández University, San Juan Campus, Carretera Alicante-Valencia Km 87, Alicante 03550, Spain Abstract 17-Estradiol elicits a rapid opposite effect on [Ca 2+ ] i in - and -cells within intact islets of Langerhans. In -cells, physiological concentrations of the gonadal hormone decreases K ATP channel activity in synergy with glucose, leading to a membrane depolarization that opens voltage-gated Ca 2+ channels, potentiating Ca 2+ signals. As a consequence insulin release is enhanced and transcription factor CREB is activated in a Ca 2+ -dependent manner. In glucagon-containing -cells, 17-estradiol provokes the abolishment of Ca 2+ oscillations generated by low glucose, a situation that should decrease glucagon release. In both types of cells the second messenger involved is cGMP. The estrogen receptor involved is located in the plasma membrane and has a pharmacological profile unrelated to classical estrogen receptors ER and ER. For that reason, it has been named non-classical membrane estrogen receptor (ncmER). Although the physiological roles of this receptor are still unknown, it may be implicated in the responses of the endocrine pancreas to the physiological and pathological changes of 17-estradiol. © 2004 Elsevier Inc. All rights reserved. Keywords: Estrogen; Endocrine; Pancreas 1. Introduction Glucose homeostasis in blood is maintained by the release of hormones from the different types of cells inte- grated in the islet of Langerhans, being insulin the most im- portant hormone involved. Pancreatic islets of Langerhans are formed by a heterogeneous population of the following cell types: insulin-releasing -cells (65–90%), glucagon releasing -cells (15–20%), somatostatin-producing -cells (3–10%), and pancreatic polypeptide producing (PP) cells (1%). Of this population, -cells have been the most stud- ied in terms of stimulus-secretion coupling. The classical stimulus-secretion coupling that drives insulin release in- volves the closure of plasma membrane ATP-dependent K + (K ATP ) channels by increasing the intracellular ATP/ADP ratio [1], diadenosine polyphosphates (DPs) [2] and cGMP [3] on account of glucose metabolism (Fig. 1). Channel ∗ Corresponding author. Tel.: +34 96 5919535; fax: +34 96 5919547. E-mail address: nadal@umh.es (A. Nadal). 1 Present address: Division of Molecular Medicine, Department of Anaesthesiology, David Geffen School of Medicine at UCLA, Los An- geles, CA 90095-7115, USA. closure induces membrane depolarization that activates voltage-operated Ca 2+ channels and Ca 2+ influx [4]. The set of channels of -cell plasma membrane generates an oscillatory electrical activity that causes [Ca 2+ ] i to oscillate [5–7]. Remarkably, the oscillatory [Ca 2+ ] i pat- tern triggers a pulsatile insulin secretion [8,9]. Membrane potential and [Ca 2+ ] i oscillations, are built as a result of the precise interplay between gap-junction conduc- tance and cell input conductance in the appropriate range [10]. As opposed to -cells, -cells release glucagon at low glucose values [11,12]. These cells contain a specific set of ion channels, responsible for their electrical activity [13,14]. In consequence [Ca 2+ ] i oscillates at low glucose concentration [7], triggering glucagon release [15]. When extracellular glucose concentration increases to the level needed for insulin release, the frequency of [Ca 2+ ] i oscil- lations decreases [7] and so does glucagon release (Fig. 1) [12]. Although the endocrine pancreas is not considered a clas- sic estrogen target, estrogen receptors are present in islets of Langerhans [16] and the effects of 17-estradiol in some physiological aspects of the islet of Langerhans have been 0039-128X/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.steroids.2004.05.010 STEROIDS: 69 (8-9): 531-536: 2004