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Current Understanding of KATP Channels in Neonatal Diseases: Focus on Insulin Secretion Disorders

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Current Understanding of KATP Channels in Neonatal Diseases: Focus on Insulin Secretion Disorders Acta Pharmacologica Sinica (2011) 32: 765–780 npg © 2011 CPS and SIMM All rights reserved 1671-4083/11 $32.00 www.nature.com/aps Review Current understanding of KATP channels in neonatal diseases: focus on insulin secretion disorders Yi QUAN1, Andrew BARSZCZYK1, Zhong-ping FENG1, *, Hong-shuo SUN1, 2, 3, 4, * Departments of 1Physiology, 2Surgery, and 3Pharmacology, 4Institute of Medical Science, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada, M5S 1A8 ATP-sensitive potassium (KATP) channels are cell metabolic sensors that couple cell metabolic status to electric activity, thus regulat- ing many cellular functions. In pancreatic beta cells, KATP channels modulate insulin secretion in response to fluctuations in plasma glucose level, and play an important role in glucose homeostasis. Recent studies show that gain-of-function and loss-of-function muta- tions in KATP channel subunits cause neonatal diabetes mellitus and congenital hyperinsulinism respectively. These findings lead to sig- nificant changes in the diagnosis and treatment for neonatal insulin secretion disorders. This review describes the physiological and pathophysiological functions of KATP channels in glucose homeostasis, their specific roles in neonatal diabetes mellitus and congenital hyperinsulinism, as well as future perspectives of KATP channels in neonatal diseases. Keywords: ATP-sensitive potassium (KATP) channels; channelopathy; neonatal diabetes; congenital hyperinsulinism; glucose homeosta- sis; diazoxide; sulfonylureas Acta Pharmacologica Sinica (2011) 32: 765–780; doi: 10.1038/aps.2011.57; published online 23 May 2011 Introduction these diseases. It also discusses the current issues associated Adenosine triphosphate (ATP)-sensitive potassium (KATP) with the use of KATP channel modulators in treating these neo- channels function as metabolic sensors that are capable of natal diseases. coupling a cell’s metabolic status to electrical activity in order to regulate many cellular functions. The KATP channels are Structure of KATP channel subunits expressed extensively in various cell types, including pan- Functional KATP channels are octomeric protein structures creatic beta cells, skeletal muscles, smooth muscles, adipose composed of four Kir6.x subunits that form the channel pore, tissue, cardiomyocytes and neurons, where they regulate cell surrounded by four sulfonylurea receptors (SURs) that regu- [1] excitability. In pancreatic beta cells, KATP channels are capable late the channel pore activity (Figure 1). The Kir6.x subunits of modulating insulin secretion in response to fluctuations in (either Kir6.1 or Kir6.2) belong to the superfamily of weak plasma glucose levels, and thus are an important regulator inwardly rectifying, voltage independent potassium (K+) [2] + of glucose homeostasis. KATP channel mutations mediated channels . These channels generate large K conductance at dysfunctions are associated with a variety of insulin secretion potentials negative to the equilibrium potential of potassium disorders, including neonatal diabetes mellitus and congenital (EK), but permit less current flow at more positive potentials. hyperinsulinism. Fortunately, the identification of the role This, in conjunction with their voltage-independence, makes of KATP channels in these diseases has led to the implementa- Kir channels one of the major regulators of resting membrane tion of new and improved clinical diagnoses and treatment potentials. Furthermore, the unique sensitivity to ATP/ADP [3] practices. This review provides an overview of KATP channels, levels makes KATP channels the ideal cell metabolic sensors . the role they play in the pathophysiology of neonatal diabe- That is, KATP channels are able to regulate the membrane excit- tes and congenital hyperinsulinism, and the new therapeutic ability in response to the metabolic status of the cell, thus, approaches developed based on our current understanding of regulating many cellular functions, such as insulin secretion, excitability and cytoprotection. [4] KATP channels were first discovered in cardiomyocytes , and * To whom correspondence should be addressed. their expression was subsequently confirmed in pancreatic E-mail [email protected] (Zhong-ping FENG); [5, 6] [7, 8] [9] [email protected] (Hong-shuo SUN) beta cells , skeletal muscles , vascular smooth muscles , [10] [11] [12–14] Received 2011-03-11 Accepted 2011-04-13 adipose tissue , glial cells , and neurons . In the major- npg www.nature.com/aps Quan Y et al 766 Figure 1. Schematic of the domain structure of a KATP channel. Four Kir6.2 subunits form the chan- nel pore, and are surrounded by four sulfonylurea receptors (SURs) that regulate pore activity. Each Kir6.2 subunit has two domains (TM1 and TM2), linked by an extracellular pore-forming region (H5). Each SUR subunit has 17 transmembrane regions grouped into three domains: TMD0 (TM1-5), TMD1 (TM 6-11), and TMD2 (TM 12-17). Each SUR subu- nit also has two nucleotide binding domains (NBD). ity of these tissues, the channel pore is formed by four Kir6.2 SUR2B. They differ only in the last 42 C-terminal amino acid subunits[15]. Each Kir6.2 subunit has two transmembrane (TM) residues. Interestingly, the C42 of SUR2B shows high homol- [20] domains (TM1 and TM2) linked by an extracellular pore-form- ogy to the C42 of SUR1 . Since most KATP channels identified [2, 3] ing region (H5) . The four TM2 domains in a KATP channel to date contain the Kir6.2 subunit, the heterogeneity observed form the channel pore and the H5 region serves as the potas- between different KATP channels mainly arises from the differ- sium selectivity filter, which contains the Kir6.2 channel sig- ential expression of SUR regulatory subunits. nature sequence GFG (rather than GYG in the K+ channel)[2]. The amino and carboxyl terminals are both found cytoplasmi- Biophysical properties and regulation of KATP channels cally, and join together to form the cytoplasmic domain that Gating and channel kinetics [2, 3, 16] is responsible for channel gating and ATP binding . Like Two independent types of gates for KATP channels have been other Kir subunits, it lacks the S4 voltage sensor region that described[3, 21, 22]. The fast gating is due to the action of the is critical for gating in all voltage dependent calcium (Ca2+), selectivity filter. This ligand-independent gate is affected + + [21] sodium (Na ) and potassium (K ) channels. Therefore, KATP by mutations near the selectivity filter . The slow ligand- channels are constitutively active if other regulatory mecha- dependent gate describes changes in the TM2 helices induced nisms, such as SUR subunits, or ATP are absent. by ATP binding[22]. Mutations in TM2 near the cytoplasmic The SUR regulatory subunits belong to the ATP-binding end have been shown to affect the slow gating in multiple [17] [3, 23–25] cassette (ABC) transporter family . Each SUR subunit has Kir channels . The kinetics of KATP channels consists of 17 TM regions, grouped into three transmembrane domains 1 open state and multiple closed states[3, 21, 26, 27]. The channel (TMDs). TMD1 (TM6-11) and TMD2 (TM12-17) are conserved only conducts current if all four Kir6.2 subunits are in the open among members of the ABC family. TMD0 (TM1-5) is unique conformation. ATP binding to any one subunit will induce a to SUR, and is essential for trafficking Kir6.2 subunits to the closed conformation in that subunit, and subsequent channel membrane surface[18]. Similar to all other ABC transport- closure. Therefore the channel has multiple closed states and ers, SUR subunits contain two nucleotide binding domains only one open state. (NBDs). Dimerization of these two NBDs creates one single nucleotide binding site and catalytic site. Mg-dependent Trafficking of ATPK channels hydrolysis at this site provides the power stroke necessary to The membrane expression of KATP channels follows the strict overcome the inhibitory effect of ATP on Kir6.2[3]. Unlike tra- 4:4 SUR:Kir stoichiometry, which has two implications. First, ditional ABC transporters, the SUR regulatory subunits cannot it allows only octameric channels expressed on the membrane, conduct a functional current[17]. thus serves as quality control mechanisms that prevent expres- Two types of SUR regulatory subunits have been identified sion of partial channels. Second, it indicates a tight coupling to date[17, 19]. They differ primarily in their affinity for sulfo- between the SUR and Kir subunits during the assembly and nylurea, their tissue distribution and genetic source. SUR1, trafficking of ATPK channels. Indeed, regulation of the mem- encoded by the ABCC8 gene located at ch11p15.1, has higher brane expression of the functional channels lies in the presence affinity for sulfonylurea and is mainly found in pancreatic of a novel ER retention signal, RKR, which is present in both beta cells and most neurons. SUR2, encoded by the ABCC9 Kir6.2 and SUR subunits[28]. Appropriate interactions between gene located at ch12p12.1, has lower affinity for sulfonylu- Kir6.2 and SUR subunits result in shielding of this RKR signal, reas and is expressed mainly in the heart, skeletal muscle and allowing the complex to exit the ER and be trafficked to the some neurons[2, 3]. SUR2 has two splice variants, SUR2A and plasma membrane. Furthermore, presence of this RKR signal Acta Pharmacologica Sinica www.chinaphar.com npg Quan Y et al 767 prevents the membrane expression of Kir tetramers (without ple, the point mutation G1479R[52, 53] in the NBD2 of SUR1 or [28] [54] SUR), SUR monomers or partial KATP channel complexes . V187D in the TMD0 of SUR1, reduced the channel respon- As such, SUR subunits are the major regulator of the traffick- siveness to ADP. The decreased ADP-mediated channel acti- ing of Kir6.2 channels. vation leads to membrane depolarization in pancreatic beta Numerous factors affect the efficiency of trafficking ofATP K cells, and continuous release of insulin into the bloodstream, channels. Specifically, SUR regulation of Kir6.2 trafficking even when plasma glucose levels are low, thus leading to is dependent on the TMD0[29] and NBD1[30] domains of SUR, hyperinsulinemic hypoglycaemia.
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