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  • >> HELLO.

  • WELCOME TO TODAY'S WEDNESDAY AFTERNOON

  • LECTURE AT NATIONAL INSTITUTES

  • OF HEALTH.

  • THANK YOU FOR COMING.

  • MY NAME IS JUSTIN TERASKA.

  • I'M AN INVESTIGATOR IN THE

  • LABORATORY OF MOLECULAR

  • BIOPHYSICS IN THE NATIONAL HEART

  • LUNG AND BLOOD INSTITUTE.

  • IT'S MY PLEASURE TO INTRODUCE

  • DR. JAMES ROTHMAN AS TODAY'S

  • WALS SPEAKER.

  • DR. ROTHMAN IS WALS PROFESSOR OF

  • BIOMEDICAL SCIENCES AND CHAIR OF

  • DEPARTMENT OF BIOMEDICAL AT

  • YALE.

  • HE'S ONE OF THE MOST INNOVATIVE

  • AND INFLUENTIAL CELL BIOLOGISTS

  • AND BUY CHEMISTS WORKING OFFER

  • THE LAST FEW DECADES.

  • DURING TENURES AT STANFORD,

  • PRINCETON, INVENTORY DEBT R,

  • COLUMBIA AN YALE, -- CLONE

  • KETTERING AND YALE, THIS IS

  • INCLUDED SEMINOLE DISCOVERIES

  • RELATED TO HOW PROTEINS INSERT

  • INTO MEMBRANES.

  • HOW VESICALES TRAFFIC THROUGH

  • THE CELL, AND HOW VESICALES FUSE

  • WITH THE MEMBRANE, A PROCESS

  • CALLED EXOCYTOSIS.

  • ASIDE FROM THE BIOLOGICAL

  • DISCOVERIES HIS LAB HAS INVENTED

  • IMPORTANT METHODS INCLUDING IN

  • VITRO RECONSTITUTION OF VESICAL

  • TRAFFICKING PATHWAYS WHICH HAS

  • REALLY ALLOWED THE COMPLEX STEPS

  • OF VESICAL TRAFFICKING TO BE

  • TEASED APART AT THEIR MOST

  • FUNDAMENTAL LEVEL H.

  • ADDITIONALLY DEVELOPED NOVEL PH

  • FLUORESCENCE PROTEINS THAT ALLOW

  • INDIVIDUAL SYNAPSES AND SINGLE

  • VESICALES TO BE WATCHED IN

  • LIVING CELLS IN REAL TIME.

  • IN PARTICULAR, DR. ROTHMAN HAS

  • HELPED TO ESTABLISH THE SNARE

  • HYPOTHESIS OF MEMBRANE FUSION

  • WHICH PROPOSES THAT THE CORRECT

  • PAIRING OF ALPHA HELICAL

  • PROTEINS ON TWO OPPOSED

  • MEMBRANES DIRECTS AND CATALYZES

  • THEIR FUSION.

  • ALONG WITH THESE IMPORTANT

  • DISCOVERIES DR. ROTHMAN MENTORED

  • AND TRAINED MANY PROMINENT

  • SUCCESSFUL BIOCHEMISTS AND CELL

  • BIOLOGISTS.

  • HE'S A MEMBER OF THE NAB

  • NATIONAL ACADEMY, INSTITUTE OF

  • MEDICINE AND RECIPIENT OF

  • NUMEROUS AWARDS INCLUDING LASTER

  • AWARD FOR BASIC SCIENCE AND

  • CAVALI PRIZE FOR NEUROSCIENCE.

  • HE WILL DISCUSS HIS RECENT WORK

  • ON SNARES AND THE ACCESSORY

  • PROTEINS THAT DIRECT THEIR

  • FUSION.

  • IN A TALK TITLED MOLECULAR

  • MECHANISMS OF SYNCHRONOUS

  • NEUROTRANSMITTER RELEASE. AFTER

  • THE SEMINAR THERE WILL BE A

  • RECEPTION IN THE LIBRARY SO

  • PLEASE COME AND THEY'LL GIVE YOU

  • AN OPPORTUNITY TO SPEAK MORE

  • INFORMALLY WITH DR. ROTHMAN.

  • JOIN ME GIVING A WARM WELCOME TO

  • JIM ROTHMAN.

  • [APPLAUSE]

  • >> THANK YOU.

  • THANKS FOR ARRANGING THE DAY,

  • BEING A GREAT HOST AND ALSO

  • SHARING WITH ME YOUR RECENT AND

  • EXCITING WORK especially on

  • novel methods used Ford

  • measuring confirmational changes

  • in proximity with fret.

  • IT'SER EXCITING, I HOPE WE CAN

  • COLLABORATE AS A RESULT OF THAT.

  • PLEASURE TO BE HERE WITH YOU

  • TODAY.

  • I'M GOING TO AS THE TITLE

  • SUGGESTS, TALK ABOUT THE PROCESS

  • OF SYNCHRONOUS NEUROTRANSMITTER

  • RELEASE.

  • THERE'S BEEN A LOT OF PROGRESS

  • OVER THE LAST FIVE YEARS I WOULD

  • SAY ESPECIALLY IN BEGINNING TO

  • UNDERSTAND THE MECHANISM BY

  • WHICH THIS VERY IMPORTANT

  • PHYSIOLOGICAL PROCESS OCCURS IN

  • STRUCTURAL AND BIOCHEMICAL

  • TERMS.

  • SO WHAT I WOULD LIKE TO DO TODAY

  • IS OFFER SOME HISTORICAL

  • BACKGROUNDS TO THE THE PROBLEMS

  • AND THEN AFTER THAT SHARE WITH

  • YOU OUR CURRENT VIEW IN THE FORM

  • OF A MODEL OF HOW A SYNCHRONOUS

  • TRANSMISSION NEUROTRANSMITTER

  • RELEASE MAY WORK.

  • A STRUCTURAL BUOY CHEMICAL MODEL

  • AND AFTER THAT SHOW YOU SOME OF

  • THE EVIDENCE ACCUMULATED FOR THE

  • MODEL OVER THE LAST TWO OR THREE

  • YEARS ESPECIALLY.

  • WHAT DO I MEAN BY SYNCHRONOUS

  • NEUROTRANSMITTER RELEASE?

  • IT'S ACTUALLY THE PHYSIOLOGISTS

  • HAVE VARIOUS COMPLEX SCHEMES TO

  • MEASURE IT AND WAYS OF DEFINING

  • IT.

  • TO ME IT'S VERY SIMPLE BUT

  • FUNDAMENTAL CONCEPT IN

  • NEUROSCIENCE WHICH IS WHEN THE

  • ACTION POTENTIAL COMES DOWN THE

  • END OF THE NERVE AND YOU RELEASE

  • A NEUROTRANSMITTER ACROSS A

  • SYNAPSE TO THE NEXT NERVE OR

  • PERHAPS MUSCLE CELL, THE

  • NEUROTRANSMITTER NEEDS TO BE

  • RELEASED AT THE RIGHT TIME.

  • WE DIDN'T WANT THE

  • NEUROTRANSMITTER TO BE RELEASED

  • ASYNCHRONOUSLY ON ITS OWN ACCORD

  • BECAUSE IN THAT CASE IT'S A

  • FALSE ALARM.

  • YOU ALSO DON'T WANT THE

  • NEUROTRANSMITTER TO GO NOT BEING

  • RELEASED BECAUSE YOU MISSED AN

  • IMPORTANT SIGNAL.

  • IN FACT WHAT YOU WANT, YOU WANT

  • THE NEUROTRANSMITTER TO BE

  • RELEASED PRECISELY SYNCHRONOUSLY

  • WITH THE ARRIVAL OF ACTION

  • POTENTIAL AT SYNAPTIC TERMINAL.

  • THE WAY THAT'S ACHIEVEED IS

  • THROUGH MEMBRANE GATED CALCIUM

  • CHANNELS, PROBABLY EVERYONE

  • KNOWS THAT ARE LOCALIZED IN THE

  • SYNAPTIC PRE-SYNAPTIC REGION

  • THAT OPENED UP THE GATE FOR

  • CALCIUM ENTRY AND IT ACTS AS A

  • SECOND MESSENGER TO TRIGGER

  • RELEASE OF NEUROTRANSMITTER

  • STORED IN VESICALES.

  • THE PROBLEM THAT WE HAVE TAKEN

  • ON THAT I WOULD LIKE TO ADDRESS

  • HERE IS NUMBER ONE HOW ARE THESE

  • VESICLES RELEASED?

  • HOW DO THEY FUSE WITH THE

  • SURROUNDING MEMBRANE HAVING

  • STORED THE NEUROTRANSMITTER

  • WITHIN THEMSELVES.

  • HOW DO THEY DO IT SO RAPIDLY?

  • SO MUCH MORE RAPIDLY, ORDERS OF

  • THE MAGNITUDE MORE RAPIDLY.

  • THAN OTHER MEMBRANE FUSION

  • PROCESSES THAT TAKE PLACE IN THE

  • CELL.

  • SO THOSE ARE THE ASPECTS BUILT

  • INTO SIN CROW IN THISTY.

  • IT'S OBVIOUSLY IMPORTANT AT A

  • GROSS LEVEL.

  • IN YOUR BRAIN IF YOUR

  • NEUROTRANSMITTERS WERE RELEASED

  • HEALTHER SETTLER, THERE WOULD BE

  • NO POSSIBILITY OF C9

  • INFORMATION PROCESSING OR

  • ANYTHING OF ANY REMOTE INTEREST.

  • YOU WOULD HAVE A -- THINK ABOUT

  • WHAT EXPERIENCE WOULD BE IF YOUR

  • VESICALES ALL FUSED AS THEY

  • SHOULD BECAUSE THE FUSION

  • PROTEINS ARE CONSTITUTIVELY

  • ACTIVE.

  • THEY SHOULD FUSE AND RELEASE

  • NEUROTRANSMITTER ALL AT ONCE SO

  • THEN YOU HAVE EVERY

  • NEUROTRANSMISSION TAKING PLACE

  • AT ONCE WITHIN A SHORT PERIOD OF

  • TIME, NO THOUGHTS WHATSOEVER OR

  • PERHAPS EVERY THOUGHT YOU WOULD

  • HAVE AND NOT BE ABLE TO

  • COMMUNICATE TO EVERYONE ELSE, IT

  • MIGHT BE AN INTENSELY

  • TRANSFORMATIONAL EXPERIENCE BUT

  • IT WOULD BE ONE THAT LASTS 10

  • MILLISECONDS.

  • SO THAT CLEARLY DOESN'T HAPPEN.

  • IN A MUCH MORE SUBTLE LEVEL THE

  • SPEED OF SYNAPTIC TRANSMISSION

  • IS VERY IMPORTANT FOR THE

  • COMPLEX CIRCUITS THAT WE HAVE.

  • IT TYPICALLY TAKES A FEW

  • MILLISECONDS FOR A SIGNAL TO BE

  • TRANSPORTED ACROSS A SYNAPSE OF

  • WHICH THE RELEASE PROCESS,

  • INITIATION OF IT TAKES TYPICALLY

  • LESS THAN A MILLISECOND IN

  • CENTRAL SYNAPSES.

  • THAT'S ACTUALLY VERY IMPORTANT

  • BECAUSE FROM THE TIME THAT A

  • PRIMARY PIECE OF POTENTIAL

  • COGNITIVE INFORMATION LIKE

  • VISUAL FIELD AND AUDITORY

  • PATTERN WHAT HAVE YOU, IS

  • SENTENCED BY OUR INPUT OUTPUT

  • DEVICES, IT HAS MAYBE 20 OR 30

  • MILLISECONDS FOR ALL THOSE

  • PATTERNS COALESCE AT YOUR

  • HIGHEST CENTERS HAVING BEEN

  • TRANSMITTED THROUGH PERHAPS TEN

  • OR 15 DIFFERENT SYNAPSES.

  • I THINK WE'RE ALL FAMILIAR WITH

  • SOME ANYWAY ARE OLD ENOUGH TO

  • REMEMBER WHAT MOVIES USED TO BE

  • LIKE WHERE THE FILM GOES BY AND

  • YOU HAVE 35, THE MAGIC NUMBER

  • FRAMES PER SECOND.

  • WHY 35?

  • BECAUSE IF IT'S FASTER THAN 35

  • IT LOOKS LIKE A CONTINUUM TO

  • YOU.

  • IF IT'S SLOWER THAN 35, YOU SEE

  • SEPARATE PICTURES.

  • HOLLYWOOD FOLKS WEREN'T SPEND

  • THRIFTS THEY WERE LOOKING FOR

  • PROFITS, SO THEY FIGURED OUT

  • THAT THE GRANULARITY OF HUMAN

  • EXPERIENCE IS ABOUT 25 OR 30

  • MILLISECONDS.

  • SO YOU CAN GET BY WITH THE LEAST

  • NUMBER OF PHOTOGRAPHIC FILM AT

  • THAT SPEED.

  • SO THAT 25, 30 MILISEDGES IS

  • WHAT YOU HAVE THAT REPRESENTS

  • SIN CROW IN THISTY AND THE JOB

  • IS TO GET THROUGH 10, 15

  • SYNAPSES AND PLOW THROUGH THEM

  • FROM HERE AND HERE UP TO HERE.

  • FAST ENOUGH.

  • HOW DOES THAT WORK IN MOLECULAR

  • TERMS?

  • THAT'S THE PROBLEM I WOULD LIKE

  • TO THE ADDRESS TODAY.

  • THE SOLUTION TO THIS PROBLEM HAS

  • COME I WOULD SAY OVER SEVERAL

  • DECADES, ACTUALLY MORE LIKE HALF

  • A CENTURY, MANY WHICH CELL

  • BIOLOGY AND NEUROSCIENCE OR

  • NEUROPHYSIOLOGY AS IT WAS THEN

  • CALLED DOVE TAILED TOGETHER,

  • GONE APART COME BACK TOGETHER

  • AND THERE'S MANY CRITICAL COMING

  • TOGETHERS OF THESE TWO FIELDS.

  • THE BEGINNING OF THIS FIELD IN

  • FACT REFLECTED THAT.

  • GOING BACK TO THE CLASSIC WORK