Discussion ion and G protein

· Reply to post from Barbara A

Explain the difference between ion channels and G proteins as they relate to signal transduction and targets of medications.

Ion channels and G proteins are crucial components of cell signal transduction mechanisms, playing different but complementary roles in mediating physiological responses. Ion channels are membrane integral proteins that facilitate the selective passage of ions through the cell membrane, leading to rapid changes in the membrane potential and subsequent cellular activity (Alexander et al., 2021). They are usually involved in processes such as the generation of action potential in neurons and muscle contraction, highlighting their meaning in excitability and neurotransmission.

In contrast, GPCS-coupled receptors start slower but longer signaling cascades after ligand connection. They activate intracellular G proteins, which in turn modulate various effects, including ions, enzymes, and other signaling channels (Duncan et al., 2020). This divergence in the action deadlines highlights the complementary nature of ion channels and G proteins within the broader context of signal transduction.

Pharmacologically, ion channels and G proteins are recognized as valuable drug targets due to their deep implications for numerous diseases. Modulation of the ion channel is essential in treating conditions such as arrhythmias, epilepsy, and chronic pain, with various small and biological molecules designed to improve or inhibit their activity (Alexander et al., 2023). Similarly, GPCRs are directed by a wide variety of medications, comprising almost a third of all marketed pharmaceutical products, due to their extensive involvement in metabolic, cardiovascular, and neuropsychiatric disorders.

Although both classes of molecules are essential in signal transduction, their mechanisms differ fundamentally. Ion channels promise rapid modulation of cellular excitability, while GPCRs offer a more subtle and prolonged response through intricate signaling waterfalls. Understanding the interaction between ion channels and G proteins is fundamental in advancing pharmaceutical strategies designed to improve various pathologies.

How would you answer the following patient question:

My grandmother has a mental illness. I have the same genes as her. Will I also get the same mental illness?

The interaction between genetics and mental illness has attracted considerable attention in recent research, underlining the double role of hereditary factors and environmental influences in modeling the results of mental health. Genetic predispositions are recognized as critical factors in the development of various mental disorders. However, these biological elements often interact with environmental variables, complicating the understanding of the etiology of mental illness.

The hereditary traits associated with mental health conditions can be traced through family stories, indicating a genetic basis for the susceptibility to disorders such as depression and anxiety (Xiao et al., 2023). However, this genetic susceptibility does not work in isolation. Environmental influences, in particular adverse childhood experiences, have shown that they influence not only individual results but also intergenerational mental health. Epel (2020) discusses how childhood adversities can lead to epigenetic changes that can affect the length of the telomers, subsequently influencing the mental health of future generations. This highlights the meaning of environmental conditions in modeling the genetic expression related to mental health.

In addition, personal experiences further clarify the complexity of the genetic-environment interaction. The individuals exposed to support environments can mitigate the risks placed by genetic vulnerabilities. On the contrary, exposure to stress or trauma in progress can exacerbate genetic predispositions, increasing the probability of developing mental illness (Xiao et al., 2023). As such, the understanding of mental health requires a nuanced approach that includes both hereditary factors and contextual realities of individuals’ lives.

In summary, the relationship between genetics and mental illness is multifaceted, underlined by hereditary susceptibility, environmental adversities and personal experiences. This global vision is essential for the development of effective preventive and therapeutic strategies in mental health assistance. Future research should continue to explore these interconnected sectors to better understand their cumulative impact on the results of mental health between generations.

 References

Alexander, S. P., Mathie, A., Peters, J. A., Veale, E. L., Striessnig, J., Kelly, E., … & Zhu, M. (2021). The

concise guide to pharmacology 2021/22: Ion channels. British Journal of Pharmacology, 178, S157-S245.

Alexander, S. P., Mathie, A. A., Peters, J. A., Veale, E. L., Striessnig, J., Kelly, E., … & Zhu, M. (2023).

The concise guide to PHARMACOLOGY 2023/24: ion channels. British Journal of Pharmacology, 180, S145-S222.

Duncan, A. L., Song, W., & Sansom, M. S. (2020). Lipid-dependent regulation of ion channels and G

Protein-coupled receptors: insights from structures and simulations. Annual review of pharmacology and toxicology, 60(1), 31-50.             

Epel, E. S. (2020). Can childhood adversity affect telomeres of the next generation? Possible

mechanisms, implications, and next-generation research. American Journal of Psychiatry, 177(1), 7-9.

Xiao, J., Jain, A., Bellia, G., Nyhan, K., & Liew, Z. (2023). A scoping review of multigenerational impacts

of grandparental exposures on mental health in grandchildren. Current Environmental Health Reports, 10(4), 369-382.

· Reply to post from Shannon

 
Ion Channels and G Proteins

 There are a few key places within the body where different medications work, and about one-third of mental health medications focus on transporters that move neurotransmitters; another third affect receptors that are linked to G proteins, while around 10% work on enzymes (Stahl, 2021). The remaining medications target various types of ion channels (Stahl, 2021). G protein-coupled receptors are important proteins found in cell membranes that can detect many signals, including ions, proteins, light, hormones, and neurotransmitters (Rehman et al., 2023). If an individual experiences problem with these receptors, such as mutations, an insufficient amount of receptors, or issues with how they signal, it can lead to various health issues that include diseases of the digestive system, nervous system, immune system, respiratory system, metabolic disorders, eye diseases, cancer, and muscle and bone issues (Rehman et al., 2023). The primary function of G protein-coupled receptors is to help transmit signals inside the cell when a molecule binds to them on the cell surface, activating the G proteins inside the cell (Rehman et al., 2023).

 Ion channels are well-organized proteins in cell membranes that are crucial to communication within cells (Dai, 2023). The ion channels within the cell membrane form tiny openings, allowing specific ions to move in and out of the cell (Dai, 2023). The ion channel acts as a doorway within the cell membrane, only allowing specific ions such as potassium, sodium, calcium, and chloride to move in and out of the cell (McGivern & Ding, 2020). These ions serve important functions in the body, such as regulating heartbeats and sending signals within the nervous system (McGivern & Ding, 2020). When these channels do not function properly, it can lead to various health issues known as channelopathies, and because of their importance in cell function, ion channels are key targets for many medications (Dai, 2023). Many important drugs used to treat psychiatric disorders target ion channels (Stahl, 2021).

The Difference Between Ion Channels and G Proteins As They Relate to Signal Transduction and Targets of Medications

 Ion channels and G proteins are essential to how cells communicate and respond to signals (Dai, 2023). While ion channels and G proteins are both important components in signal transduction, the differences between ion channels and G proteins are highlighted in the context of their roles in cell signaling and targeting of medications (Stahl, 2021). Ion channels respond to stimuli by allowing ions to pass through the cell membrane, leading to changes in the cell’s electrical state, which is critical for processes such as neuronal firing and muscle contraction (Stahl, 2021). G proteins relay signals from activated receptors on the cell surface to various intracellular targets (Stahl, 2021). Specific G proteins are activated when a ligand binds to a G protein-coupled receptor, triggering effects like opening ion channels or activating enzymes (Stahl, 2021). This process typically takes longer than ion channel activation, allowing for more prolonged and complex cellular responses (Stahl, 2021). Drugs that target ion channels can provide quick effects, which makes them useful for scenarios that require immediate medical intervention, while drugs that modulate G protein signaling can lead to more nuanced therapeutic effects since they can influence cellular responses and multiple pathways (Stahl, 2021).

Response to Patient Question

 Research indicates that mental health conditions arise from a combination of genetic, environmental, and personal factors, and genetics are not the sole factor (Kretzschmar et al., 2024). Stress and adverse life experiences can greatly affect mental health and affect how genes are expressed (Kretzschmar et al., 2024). For example, events such as intimate partner violence during pregnancy can impact the epigenome of the baby, leading to mental health problems (Kretzschmar et al., 2024). This example demonstrates how environmental factors such as relationship stressors can impact how genetic predispositions manifest in individuals (Kretzschmar et al., 2024).

 I would explain to the patient that while having a family member with a mental illness may increase their risk, it does not guarantee that they will have the same condition, that it is important to focus on maintaining a healthy lifestyle, and that early intervention and management can make a big difference if they begin to experience signs or symptoms of mental illness (Kretzschmar et al., 2024). I would be sure to reiterate to the patient that their own life experiences, support systems, and coping strategies will play a role in their mental well-being and that they are not alone and should seek support if needed (Kretzschmar et al., 2024)

References

Dai, G. (2023). Signaling by ion channels: pathways, dynamics and channelopathies. 
PubMed, 
120(5), 367–373. 
to an external site.

Kretzschmar, G. C., Boldt, A. B. W., & Targa, A. D. S. (2024). Editorial: The genetics and epigenetics of mental health. 
Frontiers in Genetics, 
15.

McGivern, J. G., & Ding, M. (2020). Ion channels and relevant drug screening approaches. 
SLAS DISCOVERY, 
25(5), 413–419.

Rehman, S., Rahimi, N., & Dimri, M. (2023, July 30). 
Biochemistry, G protein coupled receptors. StatPearls [Internet].

Stahl, S. M. (2021). 
Stahl’s Essential Psychopharmacology (5th ed.). Cambridge University Press. 
to an external site.

Respond to Augustine

Ion Channels:

Ion channels are specialized proteins integrated inside cell membranes that enable the passive transport of ions across the membrane. These ions can be categorized according to their gating modes, which comprise voltage-gated, ligand-gated, and mechanically-gated channels.

Their opening and closing modulate ion flow, which alters the cell’s electrical potential and triggers cellular responses, including muscular contraction and neurotransmitter release.

Medications that target ion channels encompass several pharmacological families, including sodium channel blockers (e.g., antiarrhythmics like lidocaine) and calcium channel blockers (e.g., used for hypertension), which alter cellular excitability and signaling cascades.

G Proteins:

G proteins (GTP-binding proteins) are intracellular proteins that convey signals from active receptors, typically GPCRs (G protein-coupled receptors), to several intracellular signaling pathways. Upon receptor activation by a ligand, the G protein exchanges GDP for GTP and dissociates into two active components: the GTP-bound alpha subunit and the beta-gamma dimer; both can subsequently initiate diverse signaling cascades, frequently involving second messengers such as cAMP or phosphatidylinositol. Pharmaceuticals that impact G proteins (such as certain antipsychotics and antidepressants) might alter receptor sensitivity or downstream signaling pathways, thereby changing mood, perception, and behavior.

Patient Inquiry Response: Genetic Susceptibility to Mental Disorders

   In discussing heritable mental illness, it is essential to stress that possessing identical genes to a family with a mental disorder may elevate an individual’s risk. Still, it does not ensure the development of the same ailment. Mental disorders arise from a complex interaction of genetic, environmental, and lifestyle influences.

Genetic Risk: Studies demonstrate that specific mental disorders possess a hereditary factor. A closer genetic relationship to an individual with a mental disease increases one’s risk, yet several individuals possess shared genetic characteristics without manifesting analogous disorders. Lin et al. (2022) indicate that several factors contribute to a complex interaction between hereditary and environmental influences in the etiology of psychiatric diseases. Regular “assortative mating” among individuals with psychiatric disorders, coupled with familial environmental transmission and multi-generational social stratification, can influence the development of environments that are associated with specific genetic variants and increase susceptibility to psychiatric conditions (Warrington, NM et al.,2023).

Environmental Influences: Elements such as life events, stress, and trauma substantially affect the manifestation of mental disease.

Repeated trauma and prolonged exposure to trauma are correlated with an elevated risk of PTSD. Researchers agree that things that happened before the traumatic event, like being abused as a child, having a family history of mental illness, having been depressed or anxious before, or having sleep problems like insomnia or nightmares, are all big reasons why people get PTSD after a traumatic event (Mao et al., 2022). Individuals who endure significant loss after a tragedy, such as the death of loved ones and the loss of possessions, are more prone to feelings of vulnerability, particularly during the initial year following a disaster.

Reference

Lin BD, Pries L-K, Sarac HS, van Os J, Rutten BPF, Luykx J, et al. Nongenetic factors associated with psychotic experiences among UK biobank participants: exposome-wide analysis and Mendelian randomization analysis. JAMA Psychiatry. 2022;79:857–868

Mao, W., Adu, M., Eboreime, E., Shalaby, R., Nkire, N., Agyapong, B., Pazderka, H., Obuobi-Donkor, G., Owusu, E., Oluwasina, F., Zhang, Y., Agyapong, V., 2022. Posttraumatic stress disorder, major depressive disorder, and wildfires: a fifth-year postdisaster evaluation among residents of Fort McMurray. Int. J. Environ. Res. Publ. Health 19 (15), 9759.

Warrington NM, Hwang L-D, Nivard MG, Evans DM. Estimating direct and indirect genetic effects on offspring phenotypes using genome-wide summary results data. Nat Commun. 2021;12:5420.