molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...

, the sulfonylurea receptors (SUR) are

membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...

s which are the molecular targets of the

sulfonylurea Sulfonylureas (UK: sulphonylurea) are a class of organic compounds used in medicine and agriculture, for example as antidiabetic drugs widely used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta ...

class of

antidiabetic Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists (liraglutide, exenatide, and others), and pramlintide, all are administered orally and are thus ...

drugs whose mechanism of action is to promote

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

release from

pancreatic The pancreas is an Organ (anatomy), organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...

beta cell Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...

s. More specifically, SUR proteins are subunits of the

inward-rectifier potassium ion channel Inward-rectifier potassium channels (Kir, IRK) are a specific lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are activated by phosphatidylinos ...

s K_ir6.x (

6.1 Surround sound is a technique for enriching the fidelity and depth of Sound recording and reproduction, sound reproduction by using multiple audio channels from speaker (electronics), speakers that surround the listener (surround channels). It ...

and 6.2). The association of four K_ir6.x and four SUR subunits form an ion conducting channel commonly referred to as the K_ATP channel. Three forms of the sulfonylurea receptor are known, SUR1 encoded by the ''ABCC8'' gene, and SUR2A and SUR2B, which are splice variants arising from a single ''ABCC9'' gene.

Function

The primary function of the sulfonylurea receptor is to sense intracellular levels of the

nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...

s ATP and ADP and in response facilitate the open or closing its associated K_ir6.x potassium channel. Hence, the K_ATP channel monitors the energy balance within the cell. Depending on the tissue in which the K_ATP channel is expressed, altering the membrane potential can trigger a variety of downstream events. For example, in pancreatic

s, high levels of glucose lead to increased production of ATP, which, in turn, binds to the K_ATP channel resulting in channel closure. The relative

depolarization In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...

(decrease in membrane hyperpolarization), in turn, opens

voltage-dependent calcium channel Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeabi ...

s increasing intracellular calcium concentrations, which triggers

exocytosis Exocytosis () is a form of active transport and bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell ('' exo-'' + ''cytosis''). As an active transport mechanism, exocytosis requires the use o ...

. Under cerebral ischemic conditions, SUR1, the regulatory subunit of the K_ATP and the NC_Ca-ATP channels, is expressed in neurons, astrocytes, oligodendrocytes, endothelial cells and by reactive microglia. Blockade of SUR1 receptors with glibenclamide has been involved in improved outcome in animal stroke models and investigational human studies by preventing brain swelling and enhancing neuroprotection.

Tissue distribution

The isoforms of the sulfonylurea receptor have the following tissue distribution: *

Adipose tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...

- SUR2B/ K_ir6.1 * Pancreatic

s - SUR1/ K_ir6.2 *

Cardiac myocytes Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate Muscle tissue, muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striat ...

- SUR2A *

Skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...

- SUR2A *

Smooth muscle Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...

- SUR2B * Brain - SUR1, SUR2A and SUR2B

Disease linkage

The SUR1 protein is coded by the ''ABCC8'' gene and is associated with

congenital hyperinsulinism Congenital hyperinsulinism is a medical term referring to a variety of congenital disorders in which hypoglycemia is caused by excessive insulin secretion.update 2013 Congenital forms of hyperinsulinemic hypoglycemia can be transient or persiste ...

and susceptibility to

type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

References

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