ADCY1

Adenylate cyclase 1 (ADCY1) is an enzyme encoded by the ADCY1 gene located on chromosome 7p12, predominantly expressed in the brain. 

This enzyme plays a crucial role in converting ATP to cyclic AMP (cAMP), a vital signaling molecule involved in various brain functions such as memory, learning, and synaptic plasticity. 

ADCY1 is regulated by calcium and calmodulin and has been implicated in the modulation of the circadian rhythm and sensory signal transduction. 

Mutations or alterations in ADCY1 can lead to a range of neurological and sensory disorders, including autosomal recessive non-syndromic sensorineural deafness and drug resistance in lung cancer. 

Overexpression of ADCY1 is linked to enhanced memory and synaptic plasticity, whereas its dysfunction is associated with cognitive impairments and conditions like autism, Fragile X syndrome, chronic pain, and mental health disorders such as bipolar disorder and schizophrenia. 

Research continues to explore ADCY1's potential as a therapeutic target and biomarker for various diseases.

What is ADCY1? [1., 5., 6., 9.] 

The ADCY1 gene is located on chromosome 7p12 and encodes the enzyme adenylate cyclase 1, a protein that is part of the adenylate cyclase family, primarily expressed in the brain. 

This protein is regulated by calcium/calmodulin levels and is involved in brain development and functions such as memory and learning. 

ADCY1 catalyzes the conversion of ATP to cAMP, a crucial signaling molecule in response to G-protein signaling. This process plays a role in various regulatory functions within the central nervous system and modulates the circadian rhythm of contrast sensitivity in the retina. 

Multiple transcript variants of ADCY1 result from alternative splicing. 

ADCY1 is also implicated in diseases such as autosomal recessive non-syndromic sensorineural deafness. 

Genetic studies have shown that overexpression of ADCY1 can enhance memory and synaptic plasticity, while mutations in ADCY1 can lead to hearing loss.

ADCY1 in Health and Disease

Memory and Learning [2., 11.] 

ADCY1 is crucial for a brain activity called long-term potentiation (LTP), which strengthens connections between nerve cells and is essential for learning and memory. 

Mice lacking ADCY1 (Adcy1−/− mice) struggle to form LTP when two high-frequency signals are spaced five minutes apart. [11.]

Additionally, ADCY1 is necessary for long-term depression (LTD), which helps the brain forget unnecessary information by weakening nerve cell connections. Adcy1−/− mice cannot perform LTD properly, showing the importance of ADCY1 in these brain processes. [11.] 

ADCY1 is also vital for creating new memories and adapting to changes. In tests where mice had to find a hidden platform in water (Morris water maze), those without ADCY1 took longer to learn the platform's location and had difficulty remembering it. [11.] 

These mice also struggled when the platform's location was changed, continuing to search in the old place instead of learning the new location, demonstrating problems with cognitive flexibility, or the ability to adapt to new situations. [11.]

ADCY1 is also associated with neuroplasticity. [4.] 

Also, overexpression of ADCY1 is associated with increased learning ability and memory. [4.] 

Hippocampal expression of ADCY1 was shown to decrease during aging, and increase during the acquisition of spatial learning. [4.] 

In summary, ADCY1 is key for making memories stable and allowing the brain to adapt by forgetting old information and learning new information. Without ADCY1, synaptic changes like LTP and LTD and memory processes do not function correctly, making it harder for the brain to learn and adapt. Thus, ADCY1 plays a crucial role in learning, memory, and cognitive flexibility.

Autism

An overproduction of ADCY1 can be seen in autism, which results in aberrant neuronal signaling by upregulating certain neuronal intracellular signaling processes; this neuronal hyperactivity is associated with autism-related symptoms. [8.] 

This neuronal hyperactivity is linked to autism-related symptoms such as repetitive behaviors, difficulty with social interactions, and an increased susceptibility to audiogenic seizures (seizures triggered by sounds). [8.] 

Fragile X Syndrome [8.] 

In Fragile X syndrome (FXS), a leading cause of autism, neurons lacking the FMRP protein show abnormal mRNA translation and signaling. 

One study identified that the absence of FMRP in neurons leads to increased translation of ADCY1 mRNA, resulting in excessive ADCY1 protein production and insensitivity to neuronal stimulation. [8.] 

Reducing ADCY1 levels in Fmr1 knockout mice normalized neuronal function and alleviated autism-related behaviors such as repetitive actions, social deficits, and audiogenic seizures. [8.] 

Deafness [7.] 

Mutations in the adenylate cyclase 1 (ADCY1) gene cause recessive hearing impairment in humans. 

The ADCY1 gene encodes a protein involved in the production of cyclic AMP (cAMP), which is crucial for mechanotransduction in the inner ear. 

A specific nonsense mutation, c.3112C>T (p.Arg1038*) results in a truncated protein lacking essential catalytic and calmodulin-binding domains, thereby reducing its enzymatic efficiency. [7.] 

This mutation causes hearing impairment, leading to symmetric, mild-to-moderate mixed hearing loss in affected individuals. 

Chronic Pain [4.] 

ADCY1 plays a crucial role in regulating pain sensitivity. Mice that lack ADCY1 are less sensitive to pain. The absence of ADCY1 affects areas in the brain, such as the hippocampal mossy fibers and the cerebellum, which are important for normal pain processing. 

This suggests that ADCY1 is essential for how pain is perceived and responded to, especially in chronic pain situations

Bipolar Disorder and Schizophrenia

ADCY1 is an enzyme that helps regulate important brain functions by integrating calcium and cAMP signaling. Research has shown that changes in ADCY1 activity are linked to mental health conditions like bipolar disorder and schizophrenia. [3., 11.]

Genetic studies have identified ADCY1 as a potential risk factor for these disorders. For instance, in schizophrenia, ADCY1 mutations are associated with impaired long-term potentiation (LTP) and abnormal spatial learning, which are crucial for cognitive functions. [3.] 

In bipolar disorder, alterations in the ADCY1 gene may affect how patients respond to lithium treatment, a common medication for mood stabilization. [3.] Individuals with certain ADCY1 variations might experience different therapeutic outcomes with lithium, highlighting the gene's role in the disorder's treatment.

Defects in ADCY1 functions are linked to cognitive impairments observed in bipolar disorder and schizophrenia. [11.]

Overall, ADCY1 plays a significant role in the brain's signaling pathways, and its dysfunction can contribute to the symptoms and treatment responses in both bipolar disorder and schizophrenia.

Sleep Deprivation

ADCY1, a Ca2+/calmodulin-sensitive enzyme, plays a critical role in generating cAMP, which is essential for various cellular processes in the brain. Studies have shown that ADCY1 is significantly involved in the brain's response to sleep deprivation.

ADCY1 expression in the brain is highest in regions like the olfactory bulb, cortex, hippocampus, thalamus, and cerebellum. [4.] Its activity is crucial for synaptic plasticity, learning, memory, and pain perception. 

In the context of sleep deprivation, genome-wide association studies (GWAS) have linked ADCY1 polymorphisms with sleep deprivation, indicating that changes in ADCY1 expression or function can affect sleep patterns and resilience to sleep loss. [4.]

The link between ADCY1 and sleep deprivation is further supported by findings that alterations in ADCY1 can disrupt the brain's normal signaling processes. Sleep deprivation can lead to increased stress on neuronal circuits, and ADCY1's role in cAMP production is essential for maintaining neuronal function and plasticity during periods of extended wakefulness.

Cancer [12.] 

In lung cancer, ADCY1 expression has been linked to chemotherapy resistance. [12.] 

The cAMP produced by ADCY1 can modulate DNA damage repair, cell proliferation, and apoptosis, which are critical factors in the effectiveness of chemotherapy. For example, cAMP can influence the expression of proteins such as Bcl-2, IAPs, and XRCC1, which are involved in apoptosis regulation and DNA repair mechanisms.

High ADCY1 expression has been associated with poor prognosis and increased drug resistance in various cancers, including non-small cell lung cancer (NSCLC). [12.] In NSCLC, ADCY1 overexpression correlates with resistance to platinum-based chemotherapy, a common treatment for advanced stages of lung cancer.

Genetic Alterations in the ADCY1 Gene

The gene for the ADCY1 protein may contain alterations or mutations that cause increase or decrease of function of the ADCY1 protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Specific SNPs Associated with Alterations in ADCY1 Function

c.3112C>T (p.Arg1038*)

This is a nonsense mutation, where the cytosine (C) at position 3112 in the coding sequence is changed to thymine (T). [5., 9.]

This mutation leads to a truncated ADCY1 protein, likely causing a loss of function. [OMIM, 

Laboratory Testing for ADCY1

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home.  

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing. Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

Frequently Asked Questions (FAQs) on ADCY1

The FAQ section addresses common questions and concerns about ADCY1, providing clear and concise answers for better understanding. 

What Is ADCY1?

ADCY1 stands for adenylate cyclase type 1, an enzyme encoded by the ADCY1 gene. This enzyme is involved in the conversion of ATP to cyclic AMP (cAMP), a crucial signaling molecule that regulates various physiological processes, including neuronal signaling and cardiac function.

Why Is ADCY1 Important?

ADCY1 is important because it plays a critical role in the cAMP signaling pathway, which is essential for various cellular processes. 

ADCY1 function is associated with memory and learning processes as well as neuroplasticity.

ADCY1 gene mutations have been linked to hearing impairment, autism, mental health disorders like schizophrenia and bipolar disorder, and even cancer progression.

What Is the Function of ADCY1?

The primary function of ADCY1 is to catalyze the conversion of ATP to cyclic AMP (cAMP) in response to various signals. 

cAMP acts as a second messenger that transmits signals from cell surface receptors to intracellular targets, modulating activities such as gene expression, enzyme activity, and ion channel function.

How Is ADCY1 Activity Measured?

ADCY1 is typically assessed as a genetic test to assess for mutations in the ADCY1 gene.

What Are Normal Levels of ADCY1 Activity?

Normal levels of ADCY1 activity can vary based on tissue type, age, and overall health, and alterations often manifest symptomatically.  

What Are the Symptoms of Abnormal ADCY1 Activity?

Symptoms of abnormal ADCY1 activity depend on whether the activity is elevated or reduced. 

High ADCY1 activity may lead to symptoms related to overactive cAMP signaling such as some of the symptoms seen in autism, fragile X syndrome, and may be noted in resistance to platinum-based chemotherapy drugs. 

Low ADCY1 activity can result in reduced sensitivity to pain, hearing problems, memory and learning problems, and some of the cognitive impairments seen in schizophrenia and bipolar disease.

Why Might a Doctor Order an ADCY1 Test?

A doctor might order an ADCY1 test to evaluate cAMP signaling in patients suspected of ADCY1 mutations. Testing can help determine the role of ADCY1 in a patient's condition and guide personalized treatment strategies.

Is the ADCY1 Test Safe?

Yes, the ADCY1 test is safe. The procedure typically involves collecting a blood or saliva sample or a cheek swab; a blood test may cause minor discomfort or bruising at the site of collection. 

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