Re: GIRK Channels
Posted: Sun Jul 17, 2016 11:55 pm
Update on the writing:
Here is a newer version of the introduction. The rest of the article is piecing together well, but is still a ways out.
Intro:
The seven 5-HT G-Protein Coupled Receptors (GPCRs) families (5-HT1-7) can be divided into three major subgroups depending on which G protein signaling pathway they activate. 5-HT1 receptors (Ex: 5-HT1A) couple mainly to the Gi/o pathway, 5-HT4-7 receptors couple to the Gs pathway, and 5-HT2 receptors activate the Gq pathway. 5HT3 receptors are inotropic ligand-gated ion channels, and therefore aren’t GPCRs.
In the Raphe Nuclei (RN), the 5HT1A receptor acts as a presynaptic somatodendritic autoreceptor. At the ends of its projections in the in the hippocampus, frontal cortex, and hypothalamus, it functions a presysnaptic autoreceptor and a postsynaptic heteroreceptor (Sotelo et al., 1990; Burnet et al., 1995; Riad et al., 2000). When more Serotonin (5-HT) is found in the synapses in the RN, activation of autoreceptors inhibits for the release of 5-HT in the projections of RN neurons (Koek et al., 1998; Gobbi et al., 2001). In this manner, 5-HT1A autoreceptors work as the major negative regulator of 5-HT activity (Albert, 2012) (Bang et al., 2012). Decreased 5-HT transmission has long been associated with Major Depressive Disorder (MDD) (Van Praag et al. 1970) and it is thought that the RN is where SSRI antidepressants exhibit their therapeutic effects. It then comes as little surprise that the 5-HT1A has been heavily implicated in effective clinical treatment of depression and anxiety. SSRIs are believed to block 5-HT reuptake by binding to SERT (5-HTT) and reducing its reuptake abilities (Murphy et al., 2004). In theory, increased somatodendritic and terminal autoreceptor binding would inhibit release of 5-HT into the synapse: resulting in no increased 5-HT levels. Through a process that is still unknown, serotonin transmission is eventually enhanced by “desensitization” of both the somatodendritic and terminal autoreceptors (Chaput et al., 1985), allowing synaptic 5-HT to accumulate in the synapse. This accounts for the characteristic 4-8 week delay between treatment origins and therapeutic relief (Gartside et al., 1995; Blier, 2010; Richardson-Jones et al., 2010).
5-HT induces hyperpolarization by activating 5-HT1A autroreceptors whose Gi/o alpha subunit activates GIRK channels located within the presynaptic membrane (Innis and Aghajian, 1987) (Bayliss, 1997) (Katayama, 1997). In the DRN, GABAB receptors use the same intracellular G-protein pathway as 5-HT1A autroreceptors: though coupling to pertussis-toxin-sensitive G-Proteins (Innis and Aghajian, 1987). Chronic treatment with the SSRI fluvoxamine reduces both 5-HT1A autoreceptor and GABAB receptor-mediated GIRK currents (Cornelisse et al., 2007). This suggests that desensitization of 5-HT1A autoreceptors by SSRI treatment occurs downstream of the receptor, and a mechanism shared with GABAB receptors.
In this literature review, I propose a G-Protein model of 5-HT1A autoreceptor desensitization occuring downstream of the receptor through GIRK channels that explains this autoreceptor desensitization. The clinical implications of understanding 5-HT1A autoreceptor disinhibition are very important in creating new-age antidepressant treatments that quickly and effectively raise 5-HT levels in patients who either cannot wait for treatments to work, or are treatment resistant to current SSRI medications. Additionally, permanent sexual changes occasionally occur in both animals and humans treated with SSRI antidepressants. Male mice who had mothers on SSRIs showed a permanent decrease in sexual drive (Gouvêa et al., 2008). Recent studies suggest that these lingering side effects are also seen in humans (Sheetrit et al., 2015) (Farnsworth et al., 2009) (Stinson, 2009) (Waldinger et al., 2015) (Leiblum et al., 2008) (Bolton et al., 2006) (Csoka et al., 2006). The implications of this persistent Post-SSRI Sexual Dysfunction (PSSD) have widespread emotional, social, and sexual implications in patients, and often leads to them to feel alienated from their peers and loved ones (Stinson, 2013). It has been hypothesized that PSSD is a result of persistent 5-HT1A desensitization after SSRI treatment has been stopped (Ghost, 2016). Understanding the mechanisms that lead to 5-HT1A desensitization could help develop treatment plans for patients with PSSD.
Here is a newer version of the introduction. The rest of the article is piecing together well, but is still a ways out.
Intro:
The seven 5-HT G-Protein Coupled Receptors (GPCRs) families (5-HT1-7) can be divided into three major subgroups depending on which G protein signaling pathway they activate. 5-HT1 receptors (Ex: 5-HT1A) couple mainly to the Gi/o pathway, 5-HT4-7 receptors couple to the Gs pathway, and 5-HT2 receptors activate the Gq pathway. 5HT3 receptors are inotropic ligand-gated ion channels, and therefore aren’t GPCRs.
In the Raphe Nuclei (RN), the 5HT1A receptor acts as a presynaptic somatodendritic autoreceptor. At the ends of its projections in the in the hippocampus, frontal cortex, and hypothalamus, it functions a presysnaptic autoreceptor and a postsynaptic heteroreceptor (Sotelo et al., 1990; Burnet et al., 1995; Riad et al., 2000). When more Serotonin (5-HT) is found in the synapses in the RN, activation of autoreceptors inhibits for the release of 5-HT in the projections of RN neurons (Koek et al., 1998; Gobbi et al., 2001). In this manner, 5-HT1A autoreceptors work as the major negative regulator of 5-HT activity (Albert, 2012) (Bang et al., 2012). Decreased 5-HT transmission has long been associated with Major Depressive Disorder (MDD) (Van Praag et al. 1970) and it is thought that the RN is where SSRI antidepressants exhibit their therapeutic effects. It then comes as little surprise that the 5-HT1A has been heavily implicated in effective clinical treatment of depression and anxiety. SSRIs are believed to block 5-HT reuptake by binding to SERT (5-HTT) and reducing its reuptake abilities (Murphy et al., 2004). In theory, increased somatodendritic and terminal autoreceptor binding would inhibit release of 5-HT into the synapse: resulting in no increased 5-HT levels. Through a process that is still unknown, serotonin transmission is eventually enhanced by “desensitization” of both the somatodendritic and terminal autoreceptors (Chaput et al., 1985), allowing synaptic 5-HT to accumulate in the synapse. This accounts for the characteristic 4-8 week delay between treatment origins and therapeutic relief (Gartside et al., 1995; Blier, 2010; Richardson-Jones et al., 2010).
5-HT induces hyperpolarization by activating 5-HT1A autroreceptors whose Gi/o alpha subunit activates GIRK channels located within the presynaptic membrane (Innis and Aghajian, 1987) (Bayliss, 1997) (Katayama, 1997). In the DRN, GABAB receptors use the same intracellular G-protein pathway as 5-HT1A autroreceptors: though coupling to pertussis-toxin-sensitive G-Proteins (Innis and Aghajian, 1987). Chronic treatment with the SSRI fluvoxamine reduces both 5-HT1A autoreceptor and GABAB receptor-mediated GIRK currents (Cornelisse et al., 2007). This suggests that desensitization of 5-HT1A autoreceptors by SSRI treatment occurs downstream of the receptor, and a mechanism shared with GABAB receptors.
In this literature review, I propose a G-Protein model of 5-HT1A autoreceptor desensitization occuring downstream of the receptor through GIRK channels that explains this autoreceptor desensitization. The clinical implications of understanding 5-HT1A autoreceptor disinhibition are very important in creating new-age antidepressant treatments that quickly and effectively raise 5-HT levels in patients who either cannot wait for treatments to work, or are treatment resistant to current SSRI medications. Additionally, permanent sexual changes occasionally occur in both animals and humans treated with SSRI antidepressants. Male mice who had mothers on SSRIs showed a permanent decrease in sexual drive (Gouvêa et al., 2008). Recent studies suggest that these lingering side effects are also seen in humans (Sheetrit et al., 2015) (Farnsworth et al., 2009) (Stinson, 2009) (Waldinger et al., 2015) (Leiblum et al., 2008) (Bolton et al., 2006) (Csoka et al., 2006). The implications of this persistent Post-SSRI Sexual Dysfunction (PSSD) have widespread emotional, social, and sexual implications in patients, and often leads to them to feel alienated from their peers and loved ones (Stinson, 2013). It has been hypothesized that PSSD is a result of persistent 5-HT1A desensitization after SSRI treatment has been stopped (Ghost, 2016). Understanding the mechanisms that lead to 5-HT1A desensitization could help develop treatment plans for patients with PSSD.