Functions of Cx36, Life or Death?
Authors: Boonyasiti Nahathai Nina , Derib‐Adugna Ahadou , Dhillon Jansher , Hameedi Herra , Inthavong Emily , Pardue Avery , Schroeder Alexandra 
Published: November 2023

In the U.S., about 2.5 million emergencies, hospitalizations, and deaths are annually related to traumatic brain injuries (TBIs). TBIs can dictate a neuron's life or death due to the transmembrane protein, connexin 36 (Cx36). Cx36 has the ability to send death signals throughout neuronal cells via gap junctions (GJ), or save surrounding tissues. A group of six transmembrane proteins form a connexon, creating half an electrical synapse (GJ). An individual protein contains 321 amino acids (AA) coded by GJD2 (human chromosomal DNA at 15q14). While 98% of its identity is shared among rat, mice, and human genomes, the developmental rate of Cx36 varies. Shared among all Cx36 isolates are the first 22–23 AA sequences, which split into four hydrophobic transmembrane domains, TM1–TM4, a cytoplasmic loop, two‐extracellular loops, and C‐ and N‐terminal cytoplasmic regions, otherwise known as the entire amino terminal domain (NT).The cytoplasmic loop and C‐terminal regions are vital because they bind structural proteins to create a complex allowing the synchronization of intercellular communication. The NT is an alpha helix which lines the GJ pore, determining GJ formation, unitary conductance, cell permeability/selectivity, and gating in response to transjunctional voltage. Overall, one gap junction features an extracellular cavity (positively charged), a transmembrane pathway (negatively charged), and a cytoplasmic opening (positively charged). In the event of a TBI, death signals or molecules, such as calcium, are transmitted through these GJs from cell to cell. Since TBIs are stressors to the brain, Cx36 could save the neurons from minor destruction via “preconditioning”. Preconditioning is when molecular signals associated with minor stressors pass through Cx36 to coupled neurons, preparing them for further insult. Current research suggests that in the absence of GJ, neuronal death is restricted, only following severe injury, limiting the amount of damage of the neurons in the brain. Researchers have conducted an experiment where the AA isoleucine 32 is replaced with arginine in an individual Cx36. Following replacement, the pore becomes inoperable due to the minor alteration inhibiting the protein's function, creating a non‐conductive channel. Therefore, apoptotic concentrations of calcium are prohibited access to other cells. Although there are advancements in the understanding of Cx36's structure and functions, it remains unclear if Cx36 is pro‐life or pro‐death. The Olathe North CBM SMART Team used 3‐D modeling and printing technology to examine structure‐function relationships of Cx36.

Support or Funding Information

Olathe North High School SMART Team

N. Boonyasiti, A. Derib‐Adugna, J. Dhillion, H. Hameedi, E. Inthavong, A. Pardue, A. Schroeder

Sponsors: C. Elniff, L.B. Fogt

Mentor: Dr. Joseph D. Fontes, Biochemistry and Molecular Biology, University of Kansas Medical Center

Functions of Cx36, Life or Death?

PDB: 2ZW3

Primary Citation: Belousov, A., & Fontes, J. (n.d.). Neuronal gap junctions: Making and breaking connections during development and injury. Trends in Neurosciences, 227–236.

This project was supported by Olathe North Life Sciences and the Milwaukee School of Engineering.