The CaSR is a sensitive receptor that binds to extracellular Ca++ and activates signaling pathways to inhibit the secretion of PTH. Even though the affinity of CaSR for extracellular Ca++ is relatively low, it can detect minute changes in extracellular [Ca++]. The relationship between [Ca++] and the rate of PTH secretion is described by a steep inverse sigmoidal curve. A difference of 0.2 mM in blood [Ca++] can span the entire curve, causing PTH secretion to vary from basal levels (5% of maximum) to maximum levels. The steady-state "setpoint" for PTH secretion varies between individuals but typically resides below the midpoint of the curve, indicating half-maximal PTH secretion. Thus, the CaSR is a rapid, robust, and continuous regulator of PTH output in response to subtle fluctuations in [Ca++].

In addition to inhibiting PTH secretion, activation of the CaSR also promotes the degradation of stored PTH in the parathyroid chief cell. This leads to the secretion of biologically inactive carboxyterminal PTH fragments from the parathyroid gland. These fragments are also produced by peripheral metabolism of PTH by the liver and kidney. Therefore, current PTH assays use two antibodies that recognize epitopes from both ends of the molecule to accurately measure intact PTH [1-84].

Over a longer timeframe, PTH production is also regulated at the level of mRNA stability and gene transcription. Decreased [Ca++] leads to the production of proteins that bind the 3-untranslated region of PTH mRNA and stabilize it, resulting in increased PTH translation. PTH gene transcription is repressed by 1,25-dihydroxyvitamin D through a negative feedback loop, acting through vitamin D response elements. The ability of 1,25-dihydroxyvitamin D to inhibit PTH gene expression is reinforced by the coordinated upregulation of CASR gene expression through positive vitamin D response elements in the CASR gene promoter region. However, during a hypocalcemic challenge, the decrease in [Ca++] overrides the inhibitory effect of 1,25-dihydroxyvitamin D on PTH transcription, allowing both hormones to be elevated simultaneously.
Fig.40.3 ).Conversely,increasingamountsofextracellularCa++ bindtotheCaSRandstimulatesignalingpathwaysthatrepressPTHsecretion.AlthoughtheCaSRbindstoextracellularCa++ withrelativelylowaffinity,theCaSRisextremelysensitivetominutechangesinextracellular[Ca++].Therelationshipbetween[Ca++]andtherateofPTHsecretionisdescribedbyasteepinversesigmoidalcurve.A0.2-mMdifferenceinblood[Ca++]spansthefullrangeofthecurve,alteringPTHsecretionfrombasal(5%ofmaximum)tomaximumlevels(
Fig.40.4).Thesteady-state“setpoint” willvarybetweenindividualsbuttypicallyresidesbelowthemidpointofthecurve(i.e.,half-maximalPTHsecretion).ThustheCaSRisarapid,robust,andcontinuousregulatorofPTHoutputinresponsetosubtle[Ca++]fluctuations.
InadditiontoinhibitingPTHsecretion,activationoftheCaSRalsopromotesdegradationofstoredPTHintheparathyroidchiefcell.Asaresult,biologicallyinactivecarboxyterminalPTHfragmentsaresecretedfromtheparathyroidglandandarealsoproducedbyperipheralmetabolismofPTHbytheliverandkidney.ThereforecurrentPTHassaysusetwoantibodiesthatrecognizeepitopesfrombothendsofthemoleculetoaccuratelymeasureintactPTH[1-84].
Overalongertimeframe,PTHproductionisalsoregulatedatthelevelofmRNAstabilityandgenetranscription(see
Fig.
40.3 ).Decreased[Ca++]leadstoproductionofproteinsthatbindthe3-untranslatedregionofPTHmRNAandstabilizeit,leadingtoincreasedPTHtranslation.PTH genetranscriptionisrepressedby1,25-dihydroxyvitaminDinanegativefeedbackloop(actingthroughvitaminDresponseelements—seelater).Theabilityof1,25-dihydroxyvitaminDtoholdPTH geneexpressionincheckisreinforcedbythecoordinatedupregulationofCASR geneexpressionbypositivevitaminDresponseelementsinthepromoterregionoftheCASR gene(see
Fig.40.3 ).Itshouldbenoted,however,thatduringahypocalcemicchallenge,thedecreasein[Ca++]overridestheinhibitoryeffectof1,25-dihydroxyvitaminDonPTHtranscription,allowingbothofthesehormonestobeelevatedsimultaneously.
•Fig. 40.3 RegulationofPTH geneexpressionandsecretion.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.)Gq + Gi PTH PTH CaSR Downstream signaling pathway 1,25 Vitamin D CaSR Ca++ proPTH preproPTH preCaSR CaSR mRNA (+) (–) (–) (–) PTH mRNA Parathyroid cell membrane Nucleus CaSR gene PTH gene •Fig. 40.4 Sigmoidalrelationshipbetweenserum[Ca++]andserumPTH,whichreflectstherateofPTHsecretion.(ModifiedfromPor-terfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.)100 50 5 1.00 1.301.201.10 1.40 Serum PTH (% of maximum) Free Ca++ in blood (mM)