Structural correlates of the creatine transporter function regulation: the undiscovered country

Abstract

Creatine (Cr) and phosphocreatine constitute an energy shuttle that links ATP production in mitochondria to subcellular locations of ATP consumption. Cells in tissues that are reliant on this energy shuttle, such as myocytes and neurons, appear to have very limited ability to synthesize creatine. Therefore, these cells depend on Cr uptake across the cell membrane by a specialized creatine transporter (CrT solute carrier SLC6A8) in order to maintain intracellular creatine levels. Cr supplementation has been shown to have a beneficial effect in numerous in vitro and in vivo models, particularly in cases of oxidative stress, and is also widely used by athletes as a performance enhancement nutraceutical. Intracellular creatine content is maintained within narrow limits. However, the physiological and cellular mechanisms that mediate Cr transport during health and disease (such as cardiac failure) are not understood. In this narrative mini-review, we summarize the last three decades of research on CrT structure, function and regulation.

Important roles of dietary taurine, creatine, carnosine, anserine and 4-hydroxyproline in human nutrition and health

“…In the small intestine of mammals including humans, the apical membrane of its enterocytes absorb dietary (luminal) creatine via Na + /Cl − -coupled (i.e., sodium-and chloridedependent) creatine transporter-1 (CreaT1) (Santacruz and Jacobs 2016). All the dietary-free creatine (100%) is absorbed by the small intestine of humans into the portal circulation (Deldicque et al 2008).…”

Creatine: a miserable life without it

“…A lack of creatine, as seen in creatine deficiency syndromes due to either genetic defects of the enzymes involved in endogenous creatine synthesis, AGAT or GAMT (Stockebrand et al 2016;Schulze et al 2016), or genetic defects in the creatine transporter (CrT) (Santacruz and Jacobs 2016;Perna et al 2016), leads to more or less severe neuromuscular and neurological phenotypes, similar to what is seen in CK-deficient (Streijger et al 2005) or creatine-depleted (GPA) animal models (Wyss and Wallimann 1994). Thus, a specific caveat should be announced here for women who consume vegan or vegetarian diets, and thus who have lower levels of total creatine in their body organs, to either switch their diet to allow for fresh meat and fish during pregnancy or to supplement with highly pure creatine in order to support healthy embryonic and neonatal development (see Wallimann et al 2011).…”

“…CrT is a two-sodium and onechloride creatine co-transporter that can be inhibited rather specifically by the creatine analogue guanidinopropionic acid (GPA). In their concise review, Santacruz and Jacobs (2016) present the facts known about CrT and provide some additional hints for possible regulatory mechanisms of CrT on the transcriptional and translational level by various signaling cascades and respective protein kinases and phosphatases, as well as by post-translational modification. In this respect, AMP-activated protein kinase (AMPK), which senses the cellular energy state by the intracellular PCr/ATP ratio, seems especially interesting.…”

Effects of high-velocity resistance training and creatine supplementation in untrained healthy aging males

“…Cr has the ability to diffuse into the mitochondria, couple with ATP produced from glycolysis and oxidative phosphorylation, and recycle (shuttle) back into the cytosol to maintain metabolic demand (Kreider et al, 2017). The shuttling of Cr from the mitochondria into the cytosol is performed using active transport, requiring the creatine transporter CRTR (Kreider et al, 2017;Santacruz & Jacobs, 2016). Once in the cytosol, creatine and its isoforms (cytosolic and glycolytic CK) meet energy requirements by maintaining ATP utilization and the cytosolic ATP/ADP ratios by rephosphorylating ADP into ATP (Kreider et al, 2017;Wallimann et al, 2011).…”