Nuclear Hormones Focus On Steroids

In contrast to the other neuroactive compounds we have discussed thus far, many hormones (including cortisol, gonadal steroids, and thyroid hormones) are able to rapidly penetrate into the lipid bilayer membrane because of their lipophilic composition (Kandel et al. 2000). Retinoic acid (vitamin A) has recently been shown to be involved in sleep, as well as learning and memory formation (Drager 2006). Nuclear receptors are transcription factors that regulate the expression of target genes in response to steroid hormones and other ligands. Approximately 50 nuclear receptors are known to exist, and their structure is defined by a number of signature functional domains. Generally, nuclear receptors comprise an amino-terminal activation function, the DNA-binding domain, a hinge region, and a carboxy-terminal ligand-binding domain containing a second activation function (Kandel et al. 2000). Upon activation by a hormone, the steroid receptor-ligand complex translocates to the nucleus, where it binds to specific DNA sequences referred to as hormone responsive elements (HREs), which subsequently regulate gene transcription (Mangelsdorf et al. 1995; Truss and Beato 1993) (see Figure 1-1). It is now known that nuclear receptors are markedly regulated by additional "accessory proteins." Nuclear receptor coregulators are cellular factors that complement nuclear receptors' function as mediators of the cellular response to endocrine signals. They are generally divisible into coregulators that promote transcriptional activation when recruited (coactivators) and those that attenuate promoter activity (corepressors).

In addition to the traditional view of steroid hormone action, it is now clear, however, that steroid hormones also have so-called nongenomic effects that include changes in neurotransmitter receptors, other membrane receptors, and second-messenger systems. These effects are less well characterized, but evidence for their existence includes modulation of neural activity in brain areas where there are few, if any, gonadal steroid receptors; there is also evidence showing that estrogen directly and rapidly inhibits calcium channels in neurons (McEwen 1999; Mermelstein et al. 1996). A growing body of data is also demonstrating bidirectional cross-talk between nuclear receptors and GPCRs. Thus, for example, gonadal steroids have long been known to modulate the activity of monoaminergic neurons and receptors. More recently, it has been shown that 3-adrenergic and dopamine Di receptors are capable of transactivating glucocorticoid and progesterone receptors, respectively. Neuroactive steroid is the term used for a steroid that is able not only to bind to its respective intracellular receptor and become rapidly translocated to the nucleus but also to alter neuronal excitability via interactions with certain neurotransmitter receptors (Rupprecht 2003) (see Figure 1-1). Many of the above-mentioned neuroactive steroids are capable of altering neuronal excitability by interacting with GABAA receptors. Studies using chimeras of GABAA/glycine receptors suggest an allosteric action of neuroactive steroids at the /V-terminal side of the middle of the second transmembrane domain of the GABA receptor |3i and/or <X2 subunits (Rick et al. 1998). However, no direct binding of the steroid to the receptor has been demonstrated. In addition to GABAA receptors, other members of the ligand-gated ion channel family (including 5-HT3, glycine, nicotinic, ACh, and glutamate receptors) have been postulated to represent targets for neuroactive steroids (Rupprecht 2003).

In view of the GABAA~enhancing potential of 3ff.-reduced neuroactive steroids, these steroids have been suggested to possess sleep-modulating or -promoting (Mendels and Chernik 1973), anticonvulsant (Frye and Scalise 2000), anxiolytic (Crawley et al. 1986), and neuroprotective (Rupprecht 2003) properties. Finally, it has been postulated that neuroactive steroids may also contribute to psychiatric symptoms sometimes observed during pregnancy and in the postpartum period (Pearson Murphy et al. 2001).

Anxiety and Panic Attacks

Anxiety and Panic Attacks

Suffering from Anxiety or Panic Attacks? Discover The Secrets to Stop Attacks in Their Tracks! Your heart is racing so fast and you don’t know why, at least not at first. Then your chest tightens and you feel like you are having a heart attack. All of a sudden, you start sweating and getting jittery.

Get My Free Ebook

Post a comment