Neuronal Signaling

Overview of Neurotransmitter Signaling Pathways

Neurotransmitters are chemical signals that relay information between nerve cells (2). They are produced by neurons and regulate the cellular physiology and activity of the recipient cells, influencing an array of neurological activities including modulating psychological states like pleasure, joy, excitement,  and learning. While the exact number of neurotransmitters remains a mystery, over 200 have been identified since 1921, and the list continues to expand (3).

Neurotransmitters transmit signals through two types of receptors: ionotropic receptors and metabotropic receptors. Ionotropic receptors have an extracellular neurotransmitter binding site and an ion channel, which allows ions to flow into cells upon neurotransmitter binding. Metabotropic receptors, also called G protein-coupled receptors (GPCRs), activate intracellular signaling proteins called heterotrimeric G proteins (1).

Major neurotransmitters and their impact on brain health and diseases

Dopamine Receptor Signaling

Dopamine is a catecholamine neurotransmitter essential to the central and peripheral nervous systems. It mediates behavioral and cognitive processes, including reward and punishment, motor behavior, motivation, sleep, dreaming, mood, learning and working memory. It signals through G protein-coupled receptors (GPCR) that may be either D1-like receptors (D1, D5) or D2-like receptors (D2, D3, D4) (4).

The D1-like receptors (D1R) stimulate adenylyl cyclase activity to increase levels of the intracellular signaling molecule cAMP, whereas the D2-like receptors inhibit adenylyl cyclase activity, thus decreasing levels of cAMP. Dysfunctional dopamine D1-like and D2-like receptor signaling is implicated in Parkinson’s disease, schizophrenia,  dyskinesias, Huntington's disease, substance use disorder, attention-deficit hyperactivity disorder (ADHD), autism and other psychiatric disorders. For this reason, dopamine receptors are relevant targets for treating psychiatric disorders (5, 6).

Endocannabinoid Developing Neuron Pathway

The endocannabinoid signaling system comprises the two major endocannabinoids (eCBs) anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG), G protein-coupled receptors CB 1 and CB 2 and regulatory enzymes and transporters (7). The endocannabinoid signaling system primarily maintains homeostasis through various mechanisms, including mediating stress response, feeding, energy metabolism and excitatory/inhibitory balance (8).

Dysregulation in the endocannabinoid system, which may be triggered by chronic stress or metabolic factors, has been associated with neurodegenerative and psychiatric disorders, including schizophrenia, major depressive disorder, anxiety disorder, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntingdon’s disease, amyotrophic lateral sclerosis and bipolar disorder. Therapeutic strategies targeting endocannabinoid system activity may help treat these diseases (9).

GABA Receptor Signaling

GABA receptor signaling is the principal inhibitory pathway in the central nervous system. It consists of GABAA and GABAB receptors and GABA-synthesizing enzymes and transporters. Its inhibitory function is necessary for brain function as it helps maintain the excitatory/inhibitory balance in the brain (10).

GABAA is an ionotropic receptor recognized as a fast synaptic inhibitor, whereas GABAB is a G-couple protein receptor known as a slow synaptic inhibitor. These receptors are found in the hippocampus, hypothalamus, thalamus, basal ganglia and brainstem (11).

Non-neurotransmitter signaling in brain health and diseases

Neuroinflammation signaling

Neuroinflammation signaling is responsible for the inflammatory responses to brain and spinal cord injury. It is mediated by the upregulation of cytokines such as IL-1β, IL-6 and TNFα, chemokines including CCL2, CCL5 and CXCL1, reactive oxygen species and secondary messengers such as nitric oxide and prostaglandins. These mediators are produced by immune cells in the central nervous system (13).

Neuroinflammation serves as a protective and self-limiting response in acute conditions which resolves after tissue repair or infection. However, it becomes detrimental when it becomes excessively and continuously activated when the inflammatory trigger persists. This hyperactivation leads to chronic inflammation, which leads to neuronal toxicity, apoptosis of neurons and oligodendrocytes and a decline in neuronal functions. A persistent inflammatory trigger may be due to internal factors like protein aggregates, external factors such as systemic infection, aging and diet and genetic predisposition such as progranulin (PGRN) mutations and apolipoprotein E4 (APOE4) mutations (14).

Ciliary neurotrophic factor  (CNTF) signaling

Ciliary neurotrophic factor (CNTF) is an interleukin-6-type cytokine expressed in glial, neuronal and non-neuronal cells, including osteoclasts, osteoblasts and osteocytes. Its receptors are CNTF receptor α (CNTFRɑ), the β-receptor glycoprotein 130 (GP130) and the leukemia inhibitor factor receptor (LIFR) (15, 16).

CNTF signaling initiates the activation of intracellular signaling pathways, including MAPK/ERK10, AKT/PI3K11 and Jak/STAT12 pathways. These pathways regulate the survival and differentiation of peripheral and central neurons, glial cells and non-neural cells. In particular, CNTF is necessary for nerve tissue development as it promotes the proliferation of neural progenitors, differentiation of sympathetic neurons, maturation of glial progenitor cells into astrocytes and oligodendrocytes and more (17).

CREB Signaling in Neurons

cAMP-responsive element binding protein (CREB) is a transcription factor that alters gene expression when triggered by elevated cAMP levels. CREB belongs to the basic leucine zipper domain (b-zip domain) family (18). It can be grouped into four functional domains: a Q1 basal transcriptional activity domain, a kinase inducible domain (KID), a glutamine-rich Q2 domain and a basic region/leucine zipper domain (bZIP). The bZIP domain mediates DNA binding and dimerization of CREB. The KID domain is activated when phosphorylated by molecules including PKA, Akt and PKC (19).

CREB activation in neurons is associated with cell proliferation, differentiation, survival, neurogenesis, memory and neuronal plasticity. CREB signaling is also implicated in the pathogenesis of mental disorders, including schizophrenia, autism, substance use disorder and depression and is a therapeutic target for these disorders (20).

References

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