Page 63 - Clinical Small Animal Internal Medicine

4 Principles of Endocrinology 31

surface. Hormone binding results in a subtle change in Evidence exists for steroid and thyroid hormone effects
VetBooks.ir the three‐dimensional structure of the receptor and this that do not involve the classic genomic signaling path­
way, and in fact, membrane receptors for both steroids
signal is carried into the cell where it is transduced into a
message(s) that affects cellular biochemistry.
Cell surface receptors can be classified by their struc­ and thyroid hormones have been identified. In addition,
these hormones may act inside cells by binding their
ture and the nature of the signaling pathway that they receptors and then the hormone–receptor complex
activate. Many protein/polypeptide hormones bind to G‐ interacts with intracellular proteins, such as transcrip­
protein (guanosine‐protein) coupled receptors. This large tion factors, without the need to bind DNA. It is believed
family of receptors possess 7‐transmembrane spanning that much of the antiinflammatory activity of glucocorti­
domains and transfer signals to another membrane pro­ coids comes about through this process, where the glu­
tein complex (the G‐protein) consisting of three subunits cocorticoid receptor complex binds to nuclear factor
(alpha, beta, and gamma). The alpha subunit at rest is kappa B (NFkappaB), preventing this molecule from
bound to a GDP, hormone‐receptor binding causes the stimulating the production of proinflammatory genes.
G‐alpha to replace the guanosine 5’‐diphosphate (GDP) In general, activation of cell surface receptors results
with guanosine 5’‐triphosphate (GTP), resulting in activa­ in rapid responses in target cells while the effects of
tion of the G‐protein and dissociation of its subunits. The steroid and thyroid hormones take longer to become
free subunits then carry the signal to other downstream apparent. This difference can be illustrated by compar­
proteins, including enzymes (e.g., adenylyl cyclase) or ion ing the response to ACTH (protein hormone) to that of
channels. Hormone activation of a G‐protein does not thyroid hormone. When performing an ACTH response
always result in activation of a cellular process, but may test, a post‐ACTH blood sample is usually collected at
instead result in inhibition. For example, some G‐alpha one hour for cortisol measurement, the time it takes for
subunits (Gi), when activated, suppress the activity of the ACTH‐induced cortisol secretion to reach maxi­
adenylyl cyclase, reducing cyclic AMP production in cells. mum levels in circulation. On the other hand, noticea­
Other types of cell surface receptors are enzymes ble clinical responses in a dog with hypothyroidism
themselves. For example, the insulin receptor has tyros­ treated with T4 replacement therapy require several
ine kinase activity, meaning that after insulin binds, the days (increase in activity) to weeks (stimulation of hair
intracellular portion of the receptor acts to place phos­ regrowth) to become apparent.
phates on tyrosine residues on the receptor itself and on
substrate molecules that contact the activated receptor.
Cell surface receptor activation can activate many Regulation of Hormone Secretion
pathways in target cells, employing signal amplification
and cross‐talk. Signaling may also reach the nucleus, Although control of each endocrine system is unique,
therefore affecting gene transcription. negative feedback is a dominant feature in most, if not
Cell surface receptor number can change with condi­ all, systems. The nature of the feedback signal depends
tions. Exposure to high levels of the activating hormone on the system; in some cases, it is an ion (calcium in the
can result in receptor downregulation and reduce the case of the parathyroid) or fuel molecule (glucose in the
target tissue response. In other situations, target cells case of insulin) while in others it is a hormone itself (cor­
express more receptors which can result in upregulation tisol in the case of the ACTH‐adrenal axis). Regulatory
of the response. In many cases, “spare receptors” are pre­ control in some systems is multifaceted and more com­
sent on targets, meaning that only a small percentage of plex; for example, regulation of aldosterone involves the
receptors need to be occupied in order to obtain a maxi­ renin‐angiotensin system with sensing mechanisms tied
mal response in the cell. to extracellular fluid volume and sodium levels. In oth­
Steroid and thyroid hormones principally affect their ers, such as calcium and parathyroid hormone, the rela­
targets by binding to intracellular receptors followed by tionship is straightforward with the parathyroid gland
movement and binding of the hormone receptor com­ responding rapidly to a decline in calcium levels in the
plex to specific regions on DNA. This binding then blood with an increase in secretion of parathyroid hor­
affects (positively or negatively) the rate of gene tran­ mone that, in turn, works to restore calcium levels to a
scription and ultimately the production of certain cell‐ set point.
specific proteins. The receptor molecules act in pairs. Feedback relationships are central to diagnostic testing
Thyroid hormone entry into target cells has been shown and to localizing disease. Dexamethasone suppression
to be mediated by specific cell membrane transporters testing relies on feedback, as this potent glucocorticoid
such as monocarboxylate transporter 8 and organic activates negative feedback in the hypothalamus and
anion transporting polypeptide 1C1. Similar transport­ pituitary, suppressing ACTH secretion and thus secretion
ers have not been identified for steroid hormones. (and therefore blood levels) of cortisol. ACTH‐secreting