The glucokinase regulatory protein (GKRP) also known as glucokinase (hexokinase 4) regulator (GCKR) is a protein produced in hepatocytes ( liver cells). GKRP binds and moves glucokinase (GK), thereby controlling both activity and intracellular location of this key enzyme of glucose metabolism. GKRP is a 68 kD protein of 626 amino acids. It is coded for by a 19

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

gene, ''GCKR'', on the short arm of chromosome 2 (2p23). GKRP was discovered by Emile van Schaftingen and reported in 1989

Physiological function

Glucokinase (GK) in liver cells phosphorylates glucose, preparing it for incorporation into

glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one o ...

or for

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...

. During periods of ample glucose supply, most GK activity can be found in the peripheral cytoplasm where glycogen synthesis is occurring. As the glucose supply declines during periods of fasting, GK activity in the cytoplasm diminishes. GKRP participates in this modulation of GK activity and location by binding free cytoplasmic GK as glucose levels decline, and moving it into the nucleus, where it is held in reserve in an inactive form. As glucose and insulin levels rise, as during digestion of a meal, GK is released from GKRP and moves back to the cytoplasm, where much of it associates with the

bifunctional enzyme Phosphofructokinase-2 ( 6-phosphofructo-2-kinase, PFK-2) or fructose bisphosphatase-2 (FBPase-2), is an enzyme indirectly responsible for regulating the rates of glycolysis and gluconeogenesis in cells. It catalyzes formation and degradation o ...

. In hepatocytes of various

mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

s, GKRP has always been found in molar excess of the amount of GK, but the GKRP:GK ratio varies according to diet,

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 ...

sufficiency, and other factors. Free GKRP shuttles between the nucleus and the cytoplasm. It may be attached to the microfilament cytoskeleton. GKRP competes with glucose to bind with GK, but inactivates it when bound. In conditions of low glucose, GKRP then pulls the GK into the nucleus. Rising amounts of glucose coming into the hepatocyte prompt the GKRP to rapidly release GK to return to the cytoplasm. GKRP itself is subject to modulation.

Fructose Fructose, or fruit sugar, is a Ketose, ketonic monosaccharide, simple sugar found in many plants, where it is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and galacto ...

and

sorbitol Sorbitol (), less commonly known as glucitol (), is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, which changes the converted aldehyde group (−CHO) to a primary alcohol g ...

can both be converted to fructose-1-phosphate, which inhibits GKRP and frees GK. Fructose 6-phosphate binds to the same site of GKRP, but enhances the ability of GKRP to bind and inactivate GK. In contrast, phosphorylation of GKRP by AMP-activated protein kinase, induced by elevated levels of AMP, reduces its capacity to inactivate GK.

Presence of GKRP in other organs

A presence and role of GKRP in other organs and tissues beyond the liver remains uncertain. Some researchers have finding small amounts of GKRP, or at least

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

coding for it, in small amounts in certain rat

lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...

cells, in

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 ...

islet cells, and in periventricular neurons of the hypothalamus in

rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' ( pack rats), ''Bandicota'' (bandicoot ...

s, but physiological function and significance in these organs are unknown.

Species differences

GKRP was originally discovered in

liver. GKRP was found to serve a similar function in livers of

mice A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

and humans as well as other animals. Cats are unusual in lacking GK activity, and have also been found to lack GKRP, though the genes for both GK and GKRP can be identified in the feline genome.

Clinical significance

Many mutant forms of human GK are associated with impaired or amplified insulin secretion or action, resulting in higher or lower blood glucose levels, and either diabetes ( MODY2) or hyperinsulinemic hypoglycemia, respectively. Some of these variants have altered interaction with GKRP, which may contribute to the hyperglycemia. The glucokinase of "

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

" who lack GKRP has a reduced expression and is entirely found in the cytoplasm. The knockout mice do not respond rapidly to glucose, exhibiting impaired glucose tolerance. Mutations of the GKRP gene (''GCKR'') in humans have been sought as possible causes of

monogenic diabetes Maturity-onset diabetes of the young (MODY) refers to any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production. MODY is often referred to as monogenic diabetes to disting ...

(

MODY Maturity-onset diabetes of the young (MODY) refers to any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production. MODY is often referred to as monogenic diabetes to disting ...

), but no examples have yet been discovered. However, variant forms of ''GCKR'' have been found to be associated with small differences in levels of glucose, insulin, triglycerides, C-reactive protein, and higher or lower risks for

type 2 diabetes mellitus 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, ...

. Activators of GK are being investigated as possible medicines for type 2 diabetes. One of the mechanisms of activation may be protection from binding by GKRP.

References

{{DEFAULTSORT:Glucokinase Regulatory Protein Proteins