molecular biology Molecular biology is a branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, biomolecular synthesis, modification, mechanisms, and interactio ...

, 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 or sulphonylureas are a class of organic compounds used in medicine and agriculture. The functional group consists of a sulfonyl group (-S(=O)2) with its sulphur atom bonded to a nitrogen atom of a ureylene group (N,N-dehydrourea ...

class of antidiabetic 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 insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

release from pancreatic

beta cell Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vi ...

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_ion_channels, lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are acti ...

s K_ir6.x ( 6.1 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 compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

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 (biology), cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolar ...

(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) with a permeability t ...

s increasing intracellular calcium concentrations, which triggers

exocytosis Exocytosis is a term for the active transport process that transports large molecules from cell to the extracellular area. Hormones, proteins and neurotransmitters are examples of large molecules that can be transported out of the cell. Exocytosis ...

. 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 (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...

- SUR2B/ K_ir6.1 * Pancreatic

s - SUR1/ K_ir6.2 *

Cardiac myocytes Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...

- SUR2A *

Skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...

- SUR2A *

Smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...

- SUR2B * Brain - SUR1, SUR2A and SUR2B

Disease linkage

The SUR1 protein is coded by the ''ABCC8'' gene and is associated with congenital hyperinsulinism and susceptibility to

type 2 diabetes Type 2 diabetes (T2D), 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 ...

References

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