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GABA's maker: What role does GAD play in the nervous system?
In the human nervous system, gamma-aminobutyric acid (GABA) is a key neurotransmitter, and an important role in its synthesis is glutamate decarboxylase (GAD). GAD is responsible for converting glutamate into GABA, a process that not only involves chemical reactions but also profoundly affects the function of the nervous system. This article will explore how GAD acts as a GABA producer and discuss its multiple roles in the nervous system.
GAD uses pyridoxine phosphate (PLP) as a cofactor to decarboxylate glutamate to generate GABA and carbon dioxide.
In mammals, GAD has two main isoforms, GAD67 and GAD65. Although the two proteins have high similarity in gene sequence, their functions are completely different. GAD67 is widely distributed inside cells and continuously supplies GABA required for non-neuronal conduction functions, such as maintaining neuronal activity and protecting against nerve damage; while GAD65 mainly synthesizes GABA at nerve endings to support the needs of nerve conduction.
In addition, there are significant differences in the expression and regulatory mechanisms of GAD67 and GAD65.
GAD67 synthesizes GABA in mitochondria to maintain basic cell functions, so it needs to remain active at almost all times, while GAD65 becomes active when required for nerve conduction.
In the brain, both forms of GAD are present at all types of synapses, including interdendritic, axon-cell body, and axon-dendritic synapses. GAD65 is thought to be dominant in the visual and neuroendocrine systems, while GAD67 may be more prevalent in neurons that are constantly active.
The functions of GAD are not limited to normal physiological processes, and its abnormal manifestations are also closely related to the development of a variety of neuropsychiatric diseases. For example, in the brains of people with autism, GAD expression is significantly downregulated, which may be related to the abnormal development of other parts of the nervous system.
Many people with autism have around 50% reduction in GAD expression in their brains, particularly in the temporal and cerebellar cortices.
In diabetes-related research, GAD67 and GAD65 are potential targets for creating immune tolerance to prevent type 1 diabetes. Research has found that injection of GAD65 can effectively prevent type 1 diabetes in mouse models, and clinical trials have shown that injection of GAD65 can preserve some insulin production in such patients.
Antibodies against GAD have also been found in other neurological disorders, such as stiff person syndrome (SPS) and schizophrenia. In SPS patients, high levels of anti-GAD antibodies indicate that the function of this enzyme is impaired, which may be a potential pathological indicator of the disease.
In the brains of schizophrenia patients, downregulated expression of GAD67 is closely related to impaired cognitive function.
In addition, GAD is closely related to the research of Parkinson's disease and cerebellar diseases. A study showed that injecting GAD into the patient's hypothalamus through a specific virus can significantly improve the condition.
It is worth noting that the existence of GAD is not limited to mammals, but this enzyme is also found in other organisms. For example, in plants, GAD is involved in responding to abiotic stresses by regulating intracellular calcium concentrations to signal changes in the external environment. This function highlights the biological diversity and importance of GAD.
As research into GAD and its role in the nervous system continues, the scientific community's understanding of this enzyme continues to deepen. Future research may reveal more links between GAD and other diseases and provide new ideas for the development of related treatments. By understanding the role of GAD, can we unlock more answers about neurological health and improve how the disease is treated?
