Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 351Bi 1 “Drugs and the Brain” Lecture 22 Revised 5/18/06Monday, May 15, 20061. Long-QT syndrome;2. Epilepsy3. Huntington’s Disease The final in-class slide (but not the posted slides) has a 1-point extra credit question. You may not communicate this question to another student; no collaboration.2Action potentials and the electrocardiogramElectrocardiogrammeasured on the skinAction Potentialmeasured with intracellularelectrodePS RTQK+ channels conductNa+ channels conduct~ 100 V~ 100 mV~ 1 sec3Monday, May 15. 2006 8:52 AM Kaiser Sunset FacilityCardiology Lab, Treadmill facilityPart of Bi1 lecturerBi1 lecturer’sbaseline EKG4An approximate explanation for the electrocardiogram, slide 1The left ventricle pumps against the greatest resistancetherefore it has thickest walls; therefore its currents are the largest; therefore it contributes most of the ECG.5An approximate explanation for the electrocardiogram, slide 2like Lecture 6CEGNa+K+Cl-extracellularcytosolCEGNa+K+Cl-ClKNaigEVdtdVCIiii,,;)(extRextextIRV The capacitive currents are largestAn extracellular electrode pair records IR drops proportional to the (absolute value) of the 1st derivative of membrane potential.6chestlegextRextextIRV Only a small fraction of the current flows across the resistance between chest and a limb.This produces a V ~ 103 times smaller than the transmembrane potential. The ECG records this signalAn approximate explanation for the electrocardiogram, slide 3CEGNa+K+Cl-extracellularintracellularCEGNa+K+Cl-extRextextIRV 7Action potentials and the electrocardiogramElectrocardiogrammeasured on the skinAction Potentialmeasured with intracellularelectrodePS RTQK+ channels conductNa+ channels conduct~ 100 V~ 100 mV~ 1 sec8ElectrocardiogramAction PotentialTwo classes of V-dependent channel explain cardiac electrophysiology in long-QT Syndrome. ~ 8 genes (complementation groups)Q-TPSRTQa heart-specific Na channel fails to inactivate completelyOr, one of several heart-specific K channels fails to activate Normal heart rhythmArrhythmia9Primary subunit Auxiliary subunitKvLQT2hERGHuman ether-a-go-go related geneKCNE2(MiRP1)A cardiac K channel is also the target for drug-induced arrhythmiasPSeldane® blocks hERG and was pulled from the market; Allegra® does not10Epilepsies: Repeated SeizuresSeizure: Massive derangement of brain function caused by excessive and synchronized function in a group of neurons. A seizure can range from a “focal” 3-sec loss of consciousness, barely noticeable (like a “space out”) . . . to a “generalized” event that causes a person to tense for several sec before a several sec jerking of his entire body. Prevalence: ~ 5% of the general population experiences one or more seizures. The repeated seizures termed epilepsy occur in ~0.5% of the population. Causes: brain injury (included a traumatic blow to the head), chronic illness, and inherited vulnerabilities .Genetics: ~ 50% of epilepsies involve an inherited vulnerability.11Epilepsies caused by Bi 1 MoleculesGenetics: ~ 50% of human epilepsies involve an inherited vulnerability.Many knockout mice have seizures. Most of these genes are not associated with human epilepsies. Nestler Table 21-3 lists ion channel defects that produce some inherited epilepsies (also discussed in Problem set 7). KNCQ, a family of K channels (loss of function). SCN, a Na channel (gain of function).CHRN, nicotinic acetylcholine receptors (gain or loss, still uncertain).Problem Set 6, Q1; see next slides. In general, the causal links are less well understood than for long-QT syndrome.12First described as a disease, 1994.The first epilepsy gene mapped and sequenced (1995). Seizures arise during phase 2 sleep (rather than “rapid eye-movement sleep”; Sometimes confused with nightmares.Some patients display abnormal brain waves (as in Nestler Figures 21-5, 21-6). Controlled by carbamazepine, not by valproateAn exemplar inherited epilepsy:Autosomal dominant nocturnal frontal lobe epilepsy.13Binding regionMembrane regionCytosolicregionColored by secondary structureColored by subunit(chain)Nearly Complete Nicotinic Acetylcholine Receptor (February, 2005)http://pdbbeta.rcsb.org/pdb/downloadFile.do?fileFormat=PDB&compression=NO&structureId=2BG9~ 2200 amino acids in 5 chains (“subunits”), MW ~ 2.5 x 106 from Lecture 3:14 How the binding of agonist (acetylcholine or nicotine) might open the channel: June 2003 viewM2M1M3M4Ligand-bindingdomainfrom Lecture 3:15ADNFLE and slow-channel myasthenic syndromeAligned Sequences of Mouse Muscle AChR M2 DomainsM2M1 M3 M42' 6' 10' 14' 18'9'Autosomal Dominant Nocturnal Frontal Lobe EpilepsyI T C I V L L S L T V F L L L I TLS LLVMMCTTGTSSSSAIIIISFNSVAVVLLLLLLSTAALLQQTTSVVVFF FFLLLLLLFLVLLILIIVAASLLVVSlow-Channel Myasthenic Syndrome:Abnormally long channel durationLLTVLX X X T C I V L L A L T V F L L L I SLS K I V22'Ligand-binding domainIC loopMuscleBrain16insideProcaine Blocks Na+ Channels from inside the cellprocaineprocaine-H+procaine-H+Functioningchannel“Trapped” or“Use-Dependent” Blocker from Lecture 8:17 Local anestheticsDental surgery (procaine = Novocain®)Sunburn medicationsAntiarrhythmics (heart) “use-dependent blocker”example: (procainamide)Antiepileptics / anticonvulsants (brain) “use-dependent blocker” (phenytoin = Dilantin® )Na+ channel blockers in medicinefrom Lecture 8:18Nicotinic acetylcholine receptorCarbamazepine, an antiepileptic drug, binds in the poreSome drugs compete with nicotine or acetylcholine~ 40 Angstroms(4 nm)transmembranedomainbased on Lecture 3:19Cystic Fibrosis1. Clinical description2. Genetics3. Gene structure4. CFTR as a protein5. Physiology of CFTR6. What’s wrong with F508?7. The cholera connection8. Selective advantage of CF?9. Therapeutic approaches:Incremental approachesGene therapyHuntington’s Disease1. Clinical description2. Genetics3. Gene structure4. Huntingtin as a protein5. Physiology of huntingtin 6. What’s wrong with the HD protein?from Lecture 2120Onset at 30-40 yr. Neurons in the striatum and cerebral cortex die, leading to movement disorders (“chorea”), dementia, and eventually