Environmental Health Perspectives is an Open Access journal published by the National Institute of Environmental Health Sciences. Environmental Health Perspectives is an Open Access journal published by the National Institute of Environmental Health Sciences.

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) support the survival and functioning of various neuronal populations. Thus, they could be attractive therapeutic agents against a multitude of neurodegenerative diseases caused by progressive death of GFLs responsive neurons. Small-molecule ligands BT13 and BT18 show an effect on GDNF family receptor GFRα1 and RET receptor tyrosine kinase RetA function. Thus, their potential binding sites and interactions were explored in the GDNF–GFRα1–RetA complex using molecular docking calculations as well as molecular dynamics (MD) simulations. Three possible regions were examined: the interface between GDNF and GFRα1 (region A), the RetA interface with GFRα1 (region B), and a possible allosteric site in GFRα1 (region C). The results obtained by the docking calculations and the MD simulations indicate that the preferable binding occurs at the allosteric site. A less preferable binding site was detected on the RetA surface interfacing GFRα1. In the membrane-bound state of RetA this can enable compounds BT13 and BT18 to act as direct RetA agonists. The analysis of the MD simulations shows hydrogen bonds for BT13 and significant hydrophobic interactions with GFRα1 for BT13 and BT18 at the allosteric site.

Plant gas exchange is regulated by guard cells that form stomatal pores. Stomatal adjustments are crucial for plant survival; they regulate uptake of CO₂ for photosynthesis, loss of water, and entrance of air pollutants such as ozone. We mapped ozone hypersensitivity, more open stomata, and stomatal CO₂-insensitivity phenotypes of the Arabidopsis thaliana accession Cvi-0 to a single amino acid substitution in MITOGEN-ACTIVATED PROTEIN (MAP) KINASE 12 (MPK12). In parallel, we showed that stomatal CO₂-insensitivity phenotypes of a mutant cis (CO₂-insensitive) were caused by a deletion of MPK12. Lack of MPK12 impaired bicarbonate-induced activation of S-type anion channels. We demonstrated that MPK12 interacted with the protein kinase HIGH LEAF TEMPERATURE 1 (HT1)—a central node in guard cell CO₂ signaling—and that MPK12 functions as an inhibitor of HT1. These data provide a new function for plant MPKs as protein kinase inhibitors and suggest a mechanism through which guard cell CO₂ signaling controls plant water management. Human activities have increased the concentrations of CO₂ and harmful air pollutants such as ozone in the troposphere. These changes can have detrimental consequences for agricultural productivity. Guard cells, which form stomatal pores on leaves, regulate plant gas exchange. To maintain photosynthesis, stomata open to allow CO₂ uptake, but at the same time, open stomata lead to loss of water and allow the entrance of ozone. Elevated atmospheric CO₂ levels reduce stomatal apertures, which can improve plant water balance but also increases leaf temperature. Using genetic approaches—in which we exploit natural variation and mutant analysis of thale cress (Arabidopsis thaliana)—we find that MITOGEN-ACTIVATED PROTEIN KINASE 12 (MPK12) and its inhibitory interaction with another kinase, HIGH LEAF TEMPERATURE 1 (HT1) (involved in guard cell CO₂ signaling), play a key role in this regulatory process. We have therefore identified a mechanism in which guard cell CO₂ signaling regulates how efficiently plants use water and cope with the air pollutant ozone.

Environmental Health Perspectives is an Open Access journal published by the National Institute of Environmental Health Sciences. Environmental Health Perspectives is an Open Access journal published by the National Institute of Environmental Health Sciences.