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GAD's Mysterious Twins: Why are GAD65 and GAD67 so different?
In mammals, two homologous proteins of glutamate decarboxylase (GAD), GAD65 and GAD67, have similar functions, but show significant differences in structure and physiological effects. These two enzymes are expressed in beta cells in the brain and pancreas and are responsible for catalyzing the conversion of glutamate into gamma-aminobutyric acid (GABA), a process that is critical for neurotransmission and various physiological functions. However, what exactly makes these two homologous proteins take different physiological pathways?
The two homologues of GAD are thought to perform different functions in different parts of the cell and at different stages of development.
Structure and mechanism
The structures of GAD65 and GAD67 are both homodimer structures and contain three main structural regions: PLP binding region, C-terminal and N-terminal regions. PLP (pyridoxal phosphate) is essential for the catalytic activity of both enzymes. This reaction is usually driven by the formation of Schiff salts and the doping of multiple amino acid residues. For GAD67, its active site is at the interactive interface between the two chains, which plays a key role in maintaining its function.The flexible ring structure of GAD65 prompts it to release PLP during transport, leading to self-inactivation. This phenomenon does not occur in GAD67.
Regulation of GAD65 and GAD67
Although there is considerable sequence similarity between the two genes, GAD65 and GAD67 have completely different roles in the body. GABA synthesis by GAD67 is required for neuronal activity, while GAD65 focuses on GABA production required for neurotransmission. In addition, GAD67 is evenly distributed in cells, while GAD65 is mainly concentrated in nerve endings.The synthesis and regulation of GAD67 and GAD65 are affected by the developmental stage and cellular microenvironment.
Role in the nervous system
These two GAD homologous proteins can be found in all types of synapses, including dendrite-dendrite, axon-soma and axon-dendrite synaptic structures. Preliminary evidence shows that GAD65 is dominant in the visual and neuroendocrine systems, while GAD67 is more abundant in continuously active neurons.Role in pathology
In recent years, studies have found that GAD65 and GAD67 show significant downregulation in the brains of patients with autism. When comparing brain samples from autism to controls, GAD65 and GAD67 expression was found to be reduced by an average of 50% and 40% in the lateral cephalic lobe and cerebellar cortex, respectively. These changes may greatly affect the cognitive and motor abilities of people with autism.These studies suggest the importance of GAD in neurodevelopment and neuropsychiatric disorders and call for further research on these enzymes.
Conclusion
Although GAD65 and GAD67 are both important enzymes for GABA production, they exhibit completely different biological functions and regulatory mechanisms. This is not only in normal physiology, but also provides a potential research perspective for revealing the correlation with various neuropsychiatric diseases. A better understanding of how these molecules interact and how they behave in different pathological conditions may pave the way for the development of new treatments.Does this mean that exploring the potential of these mysterious twins will help us unravel the mysteries of numerous diseases?
