Slow transitions between two conformational states of band 3 (AE1) modulate divalent anion transport and DBDS binding to a second site on band 3 which is activated by lowering the pH (pK 5.0)

Evidence is emerging which indicates that the anion transport activity of band 3 may be regulated. I review the molecular basis for regulation of the anion transport function of band 3 in terms of evidence showing that divalent anion transport involves a slow “hysteretic” transition between two functional states, mediated by interactions between subunits within band 3 oligomers. In addition, I briefly describe recent work from my laboratory where we have discovered a novel manifestation of slow conformational changes in band 3. This involves 4,4′-dibenzamido-2,2′-stilbenedisulfonate (DBDS) binding to a second, proton-activated site distinct from the primary stilbenedisulfonate site. This site is exposed on the outer aspect of band 3 when the pH is lowered (pK 5.0). This is the same pK as the protonation site on band 3 involved in divalent anion–proton co-transport (APCT) [J. Gen. Physiol. 79 (1982) 87]. Significantly, we have found that DBDS binding to this proton-activated site has unusually slow kinetics, and increasing DBDS concentration causes a decrease in the apparent pseudo-first-order rate constant. These results suggest that a slow conformational pre-equilibrium is the rate limiting step in DBDS binding to the proton-activated site on band 3 observed at low pH. Our results support an allosteric two-state model for regulation of divalent anion transport by band 3 oligomers involving a slow conformational transition and interactions between subunits [Biochemistry 31 (1992) 7301].     

Effect of switching from pioglitazone to the sodium glucose co-transporter-2 inhibitor dapagliflozin on body weight and metabolism-related factors in patients with type 2 diabetes mellitus: An open-label,prospective, randomized,parallel-group comparison trial

The effects of dapagliflozin (DAP) and pioglitazone (PIO) on body weight and glycaemic control were compared in patients with type 2 diabetes mellitus. Seventy-one patients on PIO were either switched to DAP (n = 36) at 5 mg per day or continued on PIO (n = 35). Primary endpoints were superiority of body weight loss and non-inferiority of HbA1c level after 24 weeks with DAP. Body weight decrease was greater with DAP than with PIO (75.3 ± 14.9 to 71.3 ± 15.1 kg vs. 74.7 ± 13.8 to 75.2 ± 13.9 kg; P < 0.01). Change in the HbA1c level was comparable (P = 0.64). The level of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and urinary albumin : creatinine ratio (ACR) decreased only with DAP (NT-proBNP, P < 0.01; ACR, P = 0.02), and the change in NT-proBNP correlated negatively with baseline NT-proBNP level (ρ = −0.68, P < 0.01) and log-converted ACR (ρ = −0.35, P < 0.05). DAP promotes body weight loss in type 2 diabetes mellitus and may decrease fluid retention, thus reducing the occurrence of cardiovascular events.