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)