Na+/K+-ATPase Modulates Purinergic P2X3 Receptor Function to Drive Bone Cancer Pain
Songqiang Huang1, Bo Peng2, Wanting Dong1
1Affiliated Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, China.
Abstract:
Bone cancer pain (BCP) is one of the most common types of chronic pain in cancer patients, with a prevalence of up to 75%. However, the pathological mechanism and therapeutic approaches are limited. Here, we demonstrated that Na+/K+-ATPase α1 (NKAα1) is a critical regulator of nociception through interaction with purinergic P2X3 receptor (P2X3R) in the dorsal root ganglion (DRG). Conditional knockout of NKAα1 in transient receptor potential vanilloid 1-positive (TRPV1+) neurons led to an increase in P2X3R-dependent Ca2+ influx and neuronal hyperexcitability and also promoted pain hypersensitivity in BCP model mice. In addition, NKAα1 knockout in TRPV1+ neurons further enhanced C-C motif chemokine ligand 5 release, thereby exacerbating spinal glial cell activation and pain hypersensitivity in BCP mice. DR5-12D, a monoclonal antibody to stabilize the expression of NKAα1, markedly inhibited the hyperexcitability of DRG nociceptors and ameliorated pain hypersensitivity in BCP mice. Overall, NKAα1 modulates P2X3R-dependent Ca2+ influx and the excitability of DRG nociceptors, thereby providing valuable theoretical guidance for the treatment of BCP.
Related Concept Videos
Hormones and Bone Tissue
Hormones That Influence Osteoblasts and/or Maintain the Matrix
Several hormones are necessary for controlling bone growth and maintaining the bone matrix. The pituitary gland secretes growth hormone (GH), which, as its name implies, controls bone growth. This happens in several ways: first, it triggers chondrocyte...
ATP Synthase: Mechanism
ATP Driven Pumps II: P-type Pumps
A typical P-type pump has three cytosolic domains: nucleotide-binding (N), phosphorylation (P), and activator (A) domains. These domains are connected to the membrane-spanning helices by short amino acid segments. ATP hydrolysis and covalent phosphoenzyme intermediate formation are crucial parts of the catalytic cycle. At the highly...
Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:
Blood and Nerve Supply to the Bones
Nutrient Artery
The nutrient artery is the main blood vessel that enters the diaphysis via the nutrient foramen. While most long bones have only one nutrient foramen, large bones, such as the femur, may have two. This...
Allosteric Proteins-ATCase
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...


