The solute/sodium symporter family (SSS family; TC 2.A.21; SLC5) consists of integral membrane proteins that use an existing sodium gradient to drive the uphill transport of various solutes, such as sugars, amino acids, vitamins, or ions across the membrane. This large family has representatives in all three kingdoms of life. The human sodium/iodide symporter (NIS) and the sodium/glucose transporter (SGLT1) are involved in diseases such as iodide transport defect or glucose-galactose malabsorption. Moreover, the bacterial sodium/proline symporter PutP and the sodium/sialic acid symporter SiaT play important roles in bacteria–host interactions. This review focuses on the physiological significance and structural and functional features of prokaryotic members of the SSS family. Special emphasis will be given to the roles and properties of proteins containing an SSS family domain fused to domains typically found in bacterial sensor kinases.

The CbrA/CbrB system is a two-component signal transduction system known to participate in the regulation of the cellular carbon/nitrogen balance and to play a central role in carbon catabolite repression in Pseudomonas species. CbrA is composed of a domain with similarity to proteins of the solute/sodium symporter family (SLC5) and domains typically found in bacterial sensor kinases. Here, the functional properties of the sensor kinase CbrA and its domains are analyzed at the molecular level using the system of the soil bacterium P. putida KT2440 as a model. It is demonstrated that CbrA can bind and transport L-histidine. Transport is specific for L-histidine and probably driven by an electrochemical proton gradient. The kinase domain is not required for L-histidine uptake by the SLC5 domain of CbrA, and has no significant impact on transport kinetics. Furthermore, it is shown that the histidine kinase can autophosphorylate and transfer the phosphoryl group to the response regulator CbrB. The SLC5 domain is not essential for these activities but appears to modulate the autokinase activity. A phosphatase activity of CbrA is not detected. None of the activities is significantly affected by L-histidine. The results demonstrate that CbrA functions as a L-histidine transporter and sensor kinase.

Histidine is an important carbon and nitrogen source of γ‐proteobacteria and can affect bacteria–host interactions. The mechanisms of histidine uptake are only partly understood. Here, we analyze functional properties of the putative histidine transporter HutT of the soil bacterium Pseudomonas putida. The hutT gene is part of the histidine utilization operon, and the gene product belongs to the amino acid‐polyamine‐organocation (APC) family of secondary transporters. Deletion of hutT severely impairs growth of P. putida on histidine, suggesting that the encoded transporter is the major histidine uptake system of P. putida. Transport experiments with cells and purified and reconstituted protein indicate that HutT functions as a high‐affinity histidine : proton symporter with high specificity for the amino acid. Substitution analyses identified amino acids crucial for HutT function.

The Chordate System administers kinetic oscillation stimulation (K.O.S) into the nasal cavity thereby potentially modulating the activity of trigemino-autonomic reflex. Modulation of this reflex has been proposed as a potential therapeutic target in migraine. The aim of this clinical trial was to evaluate the efficacy of K.O.S for the preventive treatment of chronic migraine (CM). In this randomized, double-blind, sham-controlled, multicenter clinical trial, patients with CM were treated with K.O.S once per week over a period of 6 weeks. The primary performance endpoint was the mean change in monthly headache days with moderate to severe intensity (MHDs) from the 28-day pretreatment baseline period to the performance assessment period (days 14-42 of treatment). Mean change from baseline in monthly migraine days (MMDs), proportion of participants with 30% and 50% or greater reduction in moderate to severe headache days compared with baseline, and change in the use of abortive medications from baseline were also assessed during the performance assessment period. Headache-related disability and quality-of-life measures were evaluated up to 70-day posttreatment. The primary endpoint showed a significantly larger reduction of MHD across the performance assessment period with active treatment (-3.5 days, n = 67) compared with sham (-1.2 days, n = 65) (p = 0.0132). Compared with sham, active treatment consistently also led to significant reduction of MHD during the follow-up period (-2.7 [-4.3; -1.0, p = 0.0014]) as well as of mean MMDs during the assessment (-2.4 [-4.1; -0.7, p = 0.0048]) and follow-up (-2.9 [-4.5; -1.2, p = 0.0008]) periods. 61.8% of participants reported treatment-emergent adverse events (TEAEs) with similar incidences among treatment groups (63.2% [active], 60.3% [sham]), with nasopharyngitis (8.3%), dizziness (6.3%), and epistaxis (6.3%) being the most common TEAEs. Treatment-related serious adverse events were not observed. The Chordate System provides significant benefits to patients with CM by reducing the number of MHDs. The nonpharmacologic nature of the treatment option positions K.O.S as a valuable addition to the current therapeutic portfolio for the management of CM. The trial was registered on ClinicalTrials.gov (NCT03400059) on January 17, 2018. The first patient was enrolled on March 22, 2018, and the last patient completed the study on October 1, 2022. The trial registration initially described the timing of the secondary endpoints incorrectly due to clerical error, and this was corrected to match the protocol and analysis plan once discovered. This study provides Class I evidence that weekly intranasal K.O.S is associated with a reduced number of headache days per month in patients with CM.