Last update 01 Nov 2024

SLC22A5

Last update 01 Nov 2024

Basic Info

Synonyms

CDSP, High-affinity sodium-dependent carnitine cotransporter, OCTN2

+ [5]

Introduction

Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine (PubMed:10454528, PubMed:10525100, PubMed:10966938, PubMed:17509700, PubMed:20722056). Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Relative uptake activity ratio of carnitine to TEA is 11.3 (PubMed:10454528, PubMed:10525100, PubMed:10966938). In intestinal epithelia, transports the quorum-sensing pentapeptide CSF (competence and sporulation factor) from Bacillus Subtilis wich induces cytoprotective heat shock proteins contributing to intestinal homeostasis (PubMed:18005709). May also contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable). Retained in the ER, unable to perform carnitine uptake.

Drugs associated with SLC22A5

Meldonium hydrate

Target

BBOX x SLC22A5

Mechanism

BBOX antagonists [+1]

Active Org.

Nanjing HUAXIN Biopharm. Co., Ltd. [+2]

Originator Org.-

Active Indication

Alcoholism [+4]

Inactive Indication

Cerebrovascular Disorders

Drug Highest PhaseApproved

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with SLC22A5

CTIS2023-509804-14-00 / Not yet recruitingIIT

The role of meldonium and individualized physical activities in the treatment of patients with heart failure - MELD-PHYS-2023

Start Date27 Mar 2024

Sponsor / Collaborator-

NCT06648902 / CompletedPhase 1/2IIT

A Phase 1/2 Study of the Safety and Preliminary Efficacy of Meldonium in Patients with Metastatic Renal Cell Carcinoma and Treatment-associated Fatigue.

Fatigue is a prevalent adverse event associated with systemic therapy using tyrosine kinase inhibitors (TKIs). Meldonium, a fatty acid oxidation inhibitor, modifies the carnitine pathway, a nutrient critical for fat metabolism. The World Anti-Doping Agency (WADA) classified meldonium as a banned substance due to its documented use by athletes aiming to enhance physical performance. In this study, the safety and preliminary efficacy of meldonium in treatment-related fatigue will be assessed.

Start Date01 Feb 2022

Sponsor / Collaborator-

CTR20140220 / SuspendedPhase 3

评估标准加米屈肼治疗慢性缺血性心力衰竭患者有效性和安全性的双盲、随机、安慰剂平行对照、多中心临床研究

[Translation] A double-blind, randomized, placebo-controlled, multicenter clinical study to evaluate the efficacy and safety of standard plus meldonium in the treatment of patients with chronic ischemic heart failure

主要目标：评估标准治疗加米屈肼相比较于标准治疗加安慰剂治疗慢性缺血性心衰病人 (NYHA II- III 级）的疗效次要目标：评估米屈肼治疗慢性缺血性心衰病人的安全性

[Translation]

Primary objective: To evaluate the efficacy of meldonium plus standard therapy compared with standard therapy plus placebo in patients with chronic ischemic heart failure (NYHA class II-III) Secondary objective: To evaluate the safety of meldonium in patients with chronic ischemic heart failure

Start Date14 Jul 2014

Sponsor / Collaborator

Jsc Grindeks

[+1]

100 Clinical Results associated with SLC22A5

100 Translational Medicine associated with SLC22A5

0 Patents (Medical) associated with SLC22A5

680

Literatures (Medical) associated with SLC22A5

01 Dec 2024·Biochemical Pharmacology

Carnitine traffic and human fertility

Review

Author: Mazza, Tiziano ; Galluccio, Michele ; Indiveri, Cesare ; Tonazzi, Annamaria ; Pochini, Lorena ; Scalise, Mariafrancesca ; Console, Lara ; Giangregorio, Nicola

Carnitine is a vital molecule in human metabolism, prominently involved in fatty acid β-oxidation within mitochondria. Predominantly sourced from dietary intake, carnitine also derives from endogenous synthesis. This review delves into the complex network of carnitine transport and distribution, emphasizing its pivotal role in human fertility. Together with its role in fatty acid oxidation, carnitine modulates the acety-CoA/CoA ratio, influencing carbohydrate metabolism, lipid biosynthesis, and gene expression. The intricate regulation of carnitine homeostasis involves a network of membrane transporters, notably OCTN2, which is central in its absorption, reabsorption, and distribution. OCTN2 dysfunction, results in Primary Carnitine Deficiency (PCD), characterized by systemic carnitine depletion and severe clinical manifestations, including fertility issues. In the male reproductive system, carnitine is crucial for sperm maturation and motility. In the female reproductive system, carnitine supports mitochondrial function necessary for oocyte quality, folliculogenesis, and embryonic development. Indeed, deficiencies in carnitine or its transporters have been linked to asthenozoospermia, reduced sperm quality, and suboptimal fertility outcomes in couples. Moreover, the antioxidant properties of carnitine protect spermatozoa from oxidative stress and help in managing conditions like polycystic ovary syndrome (PCOS) and endometriosis, enhancing sperm viability and fertilization potential of oocytes. This review summarizes the key role of membrane transporters in guaranteeing carnitine homeostasis with a special focus on the implications in fertility and possible treatments of infertility and other related disorders.

01 Nov 2024·International Journal of Legal Medicine

Investigating cardiac genetic background in sudden infant death syndrome (SIDS)

Article

Author: Oliva, Antonio ; Nogué-Navarro, Laia ; Fernàndez-Falgueras, Anna ; Coll, Mònica ; Cazzato, Francesca ; Brugada, Ramon ; Castellà, Josep ; Grassi, Simone ; Iglesias, Anna

AbstractSudden infant death syndrome (SIDS) is still the leading cause of death for newborns in developed countries. The pathophysiological mechanisms have not been fully clarified, but in some of SIDS cases variants of genes associated with inherited cardiac conditions are found. In this study, an analysis of SCD-related genes was performed to determine the prevalence of rare pathogenic (P) or likely pathogenic (LP) variants that could provide an unambiguous explanation for the fatal event. A cohort of 76 SIDS cases underwent Next-Generation Sequencing (NGS) analysis with a custom panel of SCD-related genes. Rare variants were classified according to the guidelines provided by the American College of Medical Genetics and Genomics (ACMG) and the specifications of the ClinGen association. Post-mortem genetic testing identified 50 (65.8%) carriers of at least one variant in SCD genes. 104 rare genetic variants were found, 65.4% in genes encoding structural proteins. Only 4 out of 76 cases (5.3%) hosted at least a P or LP variant found in genes with structural or structural/arrhythmogenic functions (SLC22A5, SCN5A, MYL3and TTN). 99 variants were classified as of uncertain significance (VUS). The difference in the distribution of variants between gene groups by function was not statistically significant (chi square, p = 0,219). Despite this, most of the variants concerned structural genes that were supposed to have a close interaction with ion channels, thus providing an explanation for the arrhythmic event. Segregation analysis, reclassification of VUS variants and identification of new associated genes could clarify the implications of the current findings.

16 Oct 2024·Biological and Pharmaceutical Bulletin

Involvement of Proton-Coupled Organic Cation Antiporter in Human Blood–Brain Barrier Transport of Mesoridazine and Metoclopramide

Article

Author: Deguchi, Yoshiharu ; Amano, Nobuyuki ; Kubo, Yoshiyuki ; Igari, Tomoko ; Hirabayashi, Hideki ; Nakakariya, Masanori ; Aoyama, Kazunobu ; Kurosawa, Toshiki ; Debori, Yasuyuki

Mesoridazine and metoclopramide are cationic drugs that are distributed in the human brain despite being substrates of multidrug resistance protein 1 (MDR1), an efflux transporter expressed at the blood-brain barrier (BBB). We investigated their transport mechanisms at the BBB using hCMEC/D3, a human cerebral microvascular endothelial cell line often used as an in vitro BBB model. The cells exhibited time- and concentration-dependent uptake of mesoridazine and metoclopramide, with K_m values of 34 and 277 µM, respectively. The uptake of both drugs significantly decreased in the presence of typical inhibitors and/or substrates of the H⁺-coupled organic cation (H⁺/OC) antiporter but not in the presence of inhibitors or substrates of organic cation transporters (OCTs), OCTN2, OATPs, SLC35F2, or the plasma membrane monoamine transporter (PMAT). Furthermore, metoclopramide uptake by hCMEC/D3 cells was pH- and energy-dependent, whereas mesoridazine uptake was unaffected by intracellular acidification and treatment with metabolic inhibitors. These results suggest that the H⁺/OC antiporter is involved in the influx of mesoridazine and metoclopramide into the brain across the BBB.

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SLC22A5

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