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Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Transport across plasma membranes is a crucial part of a cells existence. The cell membrane presents a barrier to most polar molecules, which is important for maintaining concentrations of solutes in the cytoplasm. Likewise, the membrane-bound organelles within the cell can have a specific concentration of molecules contained within; different from that of the cytoplasm or extracellular medium. However, critical substances required by the cell must have a means of entering the cell as well as the removal of waste products. This is where the key role of transmembrane transport protein comes into fruition; as they are responsible for transporting these water-soluble molecules across the plasma membrane. A given transport protein will be responsible for assisting the movement of closely related groups of organic molecule, or a specific ion, across the membrane. There are two classes of membrane transport protein: carrier proteins and channel proteins. Carrier proteins have moving parts, activated by the chemical energy source ATP, that mechanically move small molecule across the membrane. This is known as active transport. Channel proteins form a narrow hydrophilic pore that enables the passive movement of inorganic ions, known as facilitated diffusion. By these mechanisms, the cell can create large differences in composition between the internal environment and extracellular medium. This is essential for specialised cells to perform their role in the body.
Electrophysiological Recording of a Gain-of-Function Polycystin-2 Channel with a Two-Electrode Voltage Clamp
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Courtney Ng, Zhifei Wang, Bin Li, Yong Yu
Third, compared with whole-cell recording with cultured mammalian cells, TEVC recording from Xenopus oocytes can be much faster, as well as more efficient. Data from many oocytes can be collected within a relatively short period of time. Depending on the research target, the same oocyte can be recorded for minutes or longer with TEVC. Commercially available automated systems have already been able to accomplish RNA microinjection and electrophysiological measurements on oocytes fully automatically. These new technical advances allow for a high-throughput screen of potential drugs that target membrane transport proteins.
The Erythrocyte as a Cellular Model for the Clinical Investigation of Essential Hypertensive Patients
Published in Antonio Coca, Ricardo P. Garay, Ionic Transport in Hypertension: New Perspectives, 2019
Antonio Coca, Ricardo P. Garay
Membrane transport proteins were supposed to be more or less the same in different cells, including red blood cells. Therefore, it seemed reasonable to expect that either genetic or acquired defects in membrane electrolyte transport might be present in many cell types. This hypothesis was supported early on by the observation of an increased erythrocyte sodium content in essential hypertensive patients,1-2 thus confirming the findings of Tobian and Binion in vascular tissue. Moreover, the increased erythrocyte sodium content was found to be transmitted to the normotensive offspring, further supporting the genetic hypothesis.1-2
Promising strategies for improving oral bioavailability of poor water-soluble drugs
Published in Expert Opinion on Drug Discovery, 2023
Bruna Rocha, Letícia Aparecida de Morais, Mateus Costa Viana, Guilherme Carneiro
Drug absorption is primarily mediated by passive diffusion, a nonselective mechanism in the passage of substances from the intestinal lumen into the bloodstream. Passive diffusion can occur in the transcellular pathway through the enterocytes (epithelial cells), where the penetration of low-molecular-weight lipophilic molecules is facilitated. It can also occur in the paracellular pathway through the tight junctions and intercellular spaces between the enterocytes, which are especially preferred by hydrophilic drugs that do not utilize membrane transport proteins. Additionally, lymphatic absorption through the M-cells of the Peyer’s patches and some receptor and transcytosis-mediated endocytosis are alternative pathways [13]. Lastly, transporters such as the P-glycoprotein can limit absorption by stimulating the cellular efflux pump back to the intestinal lumen, reducing absorption [14]. Therefore, it is challenging to develop oral formulations of high-molecular-weight PWSDs as they have lower solubility associated with limited absorption.
Relationship between blood–brain barrier changes and drug metabolism under high-altitude hypoxia: obstacle or opportunity for drug transport?
Published in Drug Metabolism Reviews, 2023
Guiqin Liu, Xue Bai, Jianxin Yang, Yabin Duan, Junbo Zhu, Li Xiangyang
The largest and most diversified family of membrane transport proteins, the major facilitator superfamily, one of its constituents, the major facilitator superfamily domain-containing protein 2a (Mfsd2a), has three primary roles: preserving the blood–brain barrier’s integrity, preventing the transit of endothelial cells into the central nervous system, and minimizing blood–brain barrier damage (Eser et al. 2020). According to Han et al. theory’s (2022), Mfsd2a regulates blood–brain barrier permeability by controing the lipid component of blood–brain barrier endothelial cells to inhibit fossa-mediated cytocytosis and thus transport macromolecular drugs. Shang et al. (2019) identified that increased expression of HIF-1α and heme oxygenase 1 (HO-1) decreased the expression of Mfsd2a, and increased permeability of blood–brain barrier, however, it is unknown how structural and functional changes in the blood–brain barrier under high-altitude hypoxic conditions affect the transport of Mfsd2a and drugs across the blood–brain barrier.
Recent approaches to gout drug discovery: an update
Published in Expert Opinion on Drug Discovery, 2020
Naoyuki Otani, Motoshi Ouchi, Hideo Kudo, Shuichi Tsuruoka, Ichiro Hisatome, Naohiko Anzai
Membrane transport proteins, that is, transporters, are required for the hydrophilic urate to pass through cells. In the proximal tubules, for reabsorption, urate enters the cell by crossing the luminal membrane via the urate transporter 1 (URAT1) encoded by the SLC22A12 gene, and it moves across the basolateral membrane into the blood via the glucose transporter 9 (GLUT9) encoded by the SLC2A9 gene. Conversely, in the secretion of urate from blood to urine, the movement of urate into the proximal tubules via the vascular side membrane is performed by the organic anion transporter (OAT) 1 or OAT3, and its movement across the luminal side membrane to the tubular lumen for secretion into the urine is facilitated by the sodium-dependent phosphate transporter type 4 (NPT4) encoded by the SLC17A3 gene [6,25]. Other urate transporters such as ABCG2 that have been successively identified may also become new drug targets.