synthesis inhibitors such as anisomycin and actinomycin-D (Rainbow et al.
1982) can block this transcriptional effect, the so-called genomic effect of
steroids. One characteristic of the genomic effect of steroids is that its time
frame of action is typically slow, occurring over hours or days.
Not all effects of steroids are mediated by modification of gene expression. Recently, more rapid effects of steroids have been identified in
neurons and other tissues. In vivo and in vitro application of steroids
induces rapid electrophysiological changes in steroid-sensitive neurons,
including hyperpolarization of the resting membrane potential and
decreased firing rate, with a latency of milliseconds to minutes (Pfaff et al.
1971; Hua and Chen 1989; Orchinik et al. 1991; reviewed by Wong et al.
1996). Because these effects are very rapid, can be observed using cytosolfree membrane patches, and cannot be blocked by protein-synthesis
inhibitors, it is suspected that steroids can modulate the electrophysiological properties of the target cell nongenomically by acting directly on the
membrane (reviewed by Moore and Evans 1999). Accumulating evidence
suggests that circulating steroids can bind to proteinaceous receptors
located on the extracellular domain of the plasma membrane in target cells
and elicit immediate changes in the opening properties of ion channels
(Zheng and Ramirez 1994; Fig. 6.2). In some extreme cases, the ion channel
itself acts as a receptor for steroids. For example, it was recently demonstrated that estradiol binds directly to the calcium-activated K
+ channel and
increases its conductance to rapidly hyperpolarize the cell (Valverde et al.
1999). In conclusion, steroids can influence the biological function of target
cells both by acting on an intracellular receptor to change gene expression
and by acting on a membrane receptor to alter the electrophysiological
properties of a cell. The genomic actions of steroids have relatively slow
latencies and long-lasting effects, whereas nongenomic actions have short
latencies and effects that wear off more rapidly.
2.2.2. Peptide Hormones
Circulating peptide hormones typically modulate the function of target cells
by changing membrane permeability to ions, activity of enzymes, rate of
protein synthesis, and/or the cytoplasmic concentration of calcium ions.
Most peptide-induced changes that are not mediated by protein synthesis
are of short latency (e.g., within seconds to 15 minutes for changes in membrane permeability) and are short-lasting compared with genomic changes
caused by steroid hormones (e.g., days to weeks).The effects of peptide hormones are mostly mediated by guanine nucleotide binding proteins (Gproteins) and second-messenger systems that subsequently activate various
proteins via phosphorylation (Fig. 6.3). In most target cells for peptide hormones, the receptors are coupled to a G-protein that transduces the extracellular signal (i.e., binding of peptide hormones to the extracellular domain
of the receptor) into an intracellular event (i.e., increases in levels of second
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A. Yamaguchi and D.B. Kelley
1982) can block this transcriptional effect, the so-called genomic effect of
steroids. One characteristic of the genomic effect of steroids is that its time
frame of action is typically slow, occurring over hours or days.
Not all effects of steroids are mediated by modification of gene expression. Recently, more rapid effects of steroids have been identified in
neurons and other tissues. In vivo and in vitro application of steroids
induces rapid electrophysiological changes in steroid-sensitive neurons,
including hyperpolarization of the resting membrane potential and
decreased firing rate, with a latency of milliseconds to minutes (Pfaff et al.
1971; Hua and Chen 1989; Orchinik et al. 1991; reviewed by Wong et al.
1996). Because these effects are very rapid, can be observed using cytosolfree membrane patches, and cannot be blocked by protein-synthesis
inhibitors, it is suspected that steroids can modulate the electrophysiological properties of the target cell nongenomically by acting directly on the
membrane (reviewed by Moore and Evans 1999). Accumulating evidence
suggests that circulating steroids can bind to proteinaceous receptors
located on the extracellular domain of the plasma membrane in target cells
and elicit immediate changes in the opening properties of ion channels
(Zheng and Ramirez 1994; Fig. 6.2). In some extreme cases, the ion channel
itself acts as a receptor for steroids. For example, it was recently demonstrated that estradiol binds directly to the calcium-activated K
+ channel and
increases its conductance to rapidly hyperpolarize the cell (Valverde et al.
1999). In conclusion, steroids can influence the biological function of target
cells both by acting on an intracellular receptor to change gene expression
and by acting on a membrane receptor to alter the electrophysiological
properties of a cell. The genomic actions of steroids have relatively slow
latencies and long-lasting effects, whereas nongenomic actions have short
latencies and effects that wear off more rapidly.
2.2.2. Peptide Hormones
Circulating peptide hormones typically modulate the function of target cells
by changing membrane permeability to ions, activity of enzymes, rate of
protein synthesis, and/or the cytoplasmic concentration of calcium ions.
Most peptide-induced changes that are not mediated by protein synthesis
are of short latency (e.g., within seconds to 15 minutes for changes in membrane permeability) and are short-lasting compared with genomic changes
caused by steroid hormones (e.g., days to weeks).The effects of peptide hormones are mostly mediated by guanine nucleotide binding proteins (Gproteins) and second-messenger systems that subsequently activate various
proteins via phosphorylation (Fig. 6.3). In most target cells for peptide hormones, the receptors are coupled to a G-protein that transduces the extracellular signal (i.e., binding of peptide hormones to the extracellular domain
of the receptor) into an intracellular event (i.e., increases in levels of second
280
A. Yamaguchi and D.B. Kelley