The facilitative glucose transporter GLUT3: 20 years of distinction

Abstract

Glucose metabolism is vital to most mammalian cells, and the passage of glucose across cell membranes is facilitated by a family of integral membrane transporter proteins, the GLUTs. There are currently 14 members of the SLC2 family of GLUTs, several of which have been the focus of this series of reviews. The subject of the present review is GLUT3, which, as implied by its name, was the third glucose transporter to be cloned (Kayano T, Fukumoto H, Eddy RL, Fan YS, Byers MG, Shows TB, Bell GI. J Biol Chem 263: [15245][15246][15247][15248] 1988) and was originally designated as the neuronal GLUT. The overriding question that drove the early work on GLUT3 was why would neurons need a separate glucose transporter isoform? What is it about GLUT3 that specifically suits the needs of the highly metabolic and oxidative neuron with its high glucose demand? More recently, GLUT3 has been studied in other cell types with quite specific requirements for glucose, including sperm, preimplantation embryos, circulating white blood cells, and an array of carcinoma cell lines. The last are sufficiently varied and numerous to warrant a review of their own and will not be discussed here. However, for each of these cases, the same questions apply. Thus, the objective of this review is to discuss the properties and tissue and cellular localization of GLUT3 as well as the features of expression, function, and regulation that distinguish it from the rest of its family and make it uniquely suited as the mediator of glucose delivery to these specific cells.neurons; sperm; preimplantation embryo; white blood cells GLUCOSE METABOLISM IS VITAL to most mammalian cells, and the passage of glucose across cell membranes is facilitated by a family of integral membrane transporter proteins, the GLUTs. There are currently 14 members of the SLC2 family of GLUTs, several of which have been the focus of this series of reviews. The subject of the present review is GLUT3 which, as implied by its name, was the third glucose transporter to be cloned (62) and was originally designated as the neuronal glucose transporter. Together with GLUT1, -2, and -4, it comprises the Class 1 group of transporters (For review see Refs. 15,81,121). With the cloning of GLUT3, it became apparent that the brain did not rely exclusively on GLUT1 and that GLUT3 was highly and specifically expressed by neurons. Thus, GLUT3 became the third facilitative glucose transporter isoform with unique characteristics suited for cell-specific expression and function. GLUT2 is ideally suited for expression in liver and pancreas due to its high K m for glucose; GLUT4 and its translocation from intracellular vesicles to the cell surface facilitates insulin-stimulated glucose uptake in insulin-sensitive cells: muscle and fat. The overriding question that drove the early work in GLUT3 in the brain was: why would neurons need a separate glucose transporter isoform; what is it about GLUT3 that specifically suits the needs of the highly metabolic and oxidative neuron with its high glucose demand?...

<b>Immunohistochemical localization of GLUT3, MCT1, and MCT2 in the testes of mice and rats: the use of different energy sources in </b><b>spermatogenesis </b>

“…Another immunostaining study using the rat testis described the tissue sections as showing immunoreactivities for all MCT1, MCT2, and MCT4 in interstitial cells, together with MCT1 in "surrounding spermatogenic cells in the seminiferous tubules" and with MCT2 on the tails of spermatozoa (3). More recently, Mannowetz et genesis, thus providing mature sperm with GLUT3 to utilize glucose for successful fertilization (34,38). The seminiferous tubules construct a diffusion barrier against free passage to the adluminal compartment, as confirmed by the present immunostaining of the tight junction protein, ZO-1.…”

“…GLUT3 in rodents is present at high levels only in neuronal tissues (27). In addition to the brain, sperm abundantly express GLUT3; GLUT3 expressed along the entire length of the sperm tails enables the effective utilization of glucose and/or fructose (34). Sperm require a large amount of ATP, which is supplied primarily by glucose in the lumen of the female reproductive tract (2).…”

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

“…In our model, we observed that short treatments with Wnt3a did not affect the expression or localization of the major GLUT transporter described in neurons (i.e. GLUT3) (58). However, after 30 min of treatment, we observed an increase in the affinity of the transporter for the substrate.…”

Glucose transporter 3 performs a critical role in mTOR-mediated oncogenic glycolysis and tumorigenesis

“…Under physiological conditions, Glut3 is expressed predominantly in the brain tissue (2). The abnormal overexpression of Glut3 has been detected in numerous types of cancer, including breast, oral, lung, colon and bladder cancer, however, the underlying mechanism remains unclear (3)(4)(5)21).…”

“…To offset this disadvantage, the glycolytic rate in tumor cells is 100x higher than that in normal cells, and glucose uptake into tumor cells is also accelerated (1). A family of glucose transporters (Gluts) facilitates glucose movement across the plasma membranes in a tissue-specific manner, and 14 different Glut isoforms have been characterized at present (2). Glut3 is an effective glucose transporter, previous studies have demonstrated that Glut3 is upregulated in certain types of malignancy and that it is associated with poor prognosis (3,4).…”