M3-muscarinic receptor signaling pathways: therapeutic targets for diabetes?

specifically Type 2 diabetes, is increasing at such an alarming rate that it has been cited by many as a global epidemic alongside and intertwined with the obesity epidemic [1,2]. The disease is caused by defects in both insulin signaling and insulin secretion. The roles of the parasympathetic system and cholinergic input in the regulation of insulin secretion have long been established [3,4]. However, it is only recently, with the use of transgenic and knockout mice technology, that the M 3 -muscarinic receptor (M3R) has been identified as the bona fide acetylcholine receptor that is responsible for enhancing glucose-dependent insulin release in the b-cells of the islets of Langerhans in the pancreas [5]. The question is, does the determination of the role played by the M3R in insulin release provide a novel target for the treatment of diabetes? The determination of the involvement of the M3R in insulin release has occurred alongside the discovery of the cellular signaling cascades by which the M3R mediates glucose-induced insulin release. The outcome of these studies has been the intriguing observation that the M3R appears able to regulate insulin secretion via a number of distinct signaling cascades. One of these involves the protein kinase PKD1, which is activated by the phosphory lated form of the M3R in a process that results in secretory vesicle priming [6]. This protein kinase is also negatively regulated by the mitogenactivated protein kinase p38d – in this case, the M3R is proposed to stimulate insulin release by inhibiting p38d activity [7]. In another mechanism, the ability of the M3R to mediate insulin release via inositol 1,4,5-triphosphate (IP 3 )/calciumdependent signaling has been demonstrated to be modulated by the adaptor protein ankyrin-B. Here, ankyrin-B modulates M3R-mediated insulin release by binding to, and thus stabilizing, IP 3 receptors in b-cells [8]. Pancreatic islets from heterozygous ankyrin-B-mutant (ankB) mice exhibited a reduction in both basal and carbachol-stimulated intracellular calcium release [8], suggesting that the IP 3 receptor is stabilized in the open state. The M3R has also been demonstrated to activate a sodium channel, designated the sodium leak channel nonselective M3-muscarinic receptor signaling pathways: therapeutic targets for diabetes?