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1 . rhodopsin was known since the 1930s to be an integral membrane protein , only removable and purified in micelles from retinas using detergent solubilization .
its initial purple color was early discovered to be  bleached  by light into the colorless metarhodopsin ii , a product subsequently found to be the actual active end product of light action on the rod visual receptor pigment .
2 . visual cell membranes : vertebrate photoreceptor cells are long cylinders whose outer segments contain a cylindrical stack of 500 to 2000 of orthogonal golgi - like flattened membrane saccules ( lamellar disks ) .
these disks , in rods , are separated from the ion channel - containing plasma membrane and are optimally designed to absorb longitudinally propagating light via the massive number ( 10 - 10 ) of visual pigment molecules embedded in them .
an outer segment attaches to the rest of the cell via a single cilium from which it is easily broken away .
we collected these in physiologic media in complete darkness and mounted them for study by msp as they lay on their long cylindrical axes in the plane of a microscope slide .
visual pigment is bleached by absorbed light ( lose its visible spectrum ) with near 100% efficiency .
both rod and cone cells are microscopically small in the service of spatial resolution of vision and therefore contain only a tiny amount of visual pigment . to measure the presence of such tiny amounts of photosensitive visual pigment ( gpcr ) molecules by msp , we had to use extremely dim monochromatic light and the extraordinarily sensitive msp instrument that i developed .
our msp spectra showed that rhodopsins are embedded in a highly oriented manner in the outer segment membranes ; preferentially absorbing only light whose electric polarization is perpendicular to the cellular cylinder axis ( within the disk membrane planes ) .
the ability of rhodpsin to maintain such preferential orientation in disk membranes is consistent with its integral structural role as part of those membranes as well as explaining the efficiency of physiological light capture for vision via optimum orientation of its chromophoric electric vectors .
proteins in lipid : my msp measurements on single rods found ca . 3 mm ( ! ) rhodopsin in a 2-d ( liquid ) crystalline lattice , a molecular density of ca .
such packing density places adjacent rhodopsins only about one rhodopsin diameter apart and leaves room for only about one boundary layer of lipid molecules per rhodopsin ( 2 lipid diameters between adjacent rhodopsins ) .
5 . discovery of a protein motion : msp of most cone cells required use of ~1m wide optical microbeams .
we repeatedly noted more rapid bleaching by the 1m measuring light in smaller cells and less rapid pigment loss when using the same sized microbeam in larger cells .
this was puzzling for some time ( there was no hint at that time that proteins could move around in membranes ) until we gradually realized that molecules being bleached by small microbeams in large cells might in fact be getting replaced by molecules moving from the still - dark portion of each cellular disk membrane .
this  preserving  effect vanished when cells were prepared in glutaraldehyde - containing media as expected if previously mobile molecules were being cross - linked .
lateral diffusion : to determine the speed of this diffusional pigment movement , we needed to rebuild our microscope to allow microbeam flash photolysis on one side of the cell while measuring at other locations within the cell .
these studies showed that rod visual pigment moves within seconds in the planes of the lamellar disc membranes we used these data to calculate a lateral diffusion coefficient of about 0.5m / sec for visual receptor pigment motion .
we also determined that the previously puzzling beam - width dependence of bleaching speed was only laterally directed ( side to side in the rod cylinder ) and did not occur in the longitudinal ( axial ) direction .
we called this  lateral diffusion .  at this time , no one had any idea that rods were also replete with g proteins and other signaling proteins .
gain / amplification : several years later , in separate experiments designed to test for ca release that might mediate light activation of rods , i discovered instead the near - instantaneous light activation of cyclic gmp ( cgmp ) hydrolysis that led rapidly to our understanding that rhodopsin is an enzyme that causes many copies of its substrate , transducin or gt , to become activated and in turn , to activate many copies of cgmp phosphodiesterase ( pde ) .
initially , though activity required gtp cofactor , we were measuring only pde activity via loss of cgmp .
but our further development of fast filtration and reaction quenching methods allowed us to simultaneously titrate the speed and magnitude ( amplification gain ) of radiolabeled gtp binding vs light intensity directly .
we early noted that onset speed of pde activation became faster and faster with brighter flashes ( more bleached rhodopsin ) and slowed down to a limiting onset speed as the light was made dimmer and dimmer .
these activity onset curves were always precisely parabolic ( a = kt ) with characteristic delay time of a couple of seconds to reach maximal pde activity after very weak bleaches .
we quickly noted that this timing corresponded closely to my earlier measurements of rhodopsin lateral diffusion speed as well as to the theretofore puzzling parabolic time delay of rod electrical responses to single photons .
membrane real estate : we performed quantitative analysis of complete light titration curves of pde velocity and of gtp binding .
activity saturation of these curves showed that single photons were activating membrane regions ( domains ) near the size of an entire rod disk membrane .
but final activity was always parabolically delayed by a constant time for all the weakest lights below a limiting level comparable to the time it would take a single activated rhodopsin to carry activation to other proteins via its lateral diffusion . 10 .
signal transduction via lateral diffusion mediated amplifier of vision : the size of single photon activation domains that we determined together with their congruent parabolic activity delay corresponding with both lateral diffusion and receptor electrical response delay times at the weakest light stimulus , thus gave birth to our r*g * lateral diffusion amplifier hypothesis of vision .
we had found that pde activation and its preceding g protein activation had the single photon sensitivity , the gain / amplification of coupled rapid enzymatic activation , and the parabolic activation delay time ( speed ) of lateral diffusional reaction partner mixing consistent with the sought after parameters of visual transduction .
the role of stoichiometry of components : we found the number of activated g proteins to exceed the number of activated pde s on disk membranes by about their known static concentration ratio ( ~5:1 ) . a 5-fold stoichiometric excess of gtpase over pde would increase the yield of an intrinsically weak stoichiometric binding between g * and p on the membrane surface .
reaction speed : the 5:1 ratio of g*/p would simultaneously decrease the time needed for activated gtpases to collide with pdes by 5-fold if proteins diffused at comparable speed while fixed to the membrane surfaces .
thus , diffusional delay between r * and p activation would be only trivially longer than that for g itself .
g and p are peripheral membrane proteins inserted largely via their long chain fatty acids . at the time of our discoveries , such peripheral proteins
were speculated to be able to accelerate their lateral diffusion via  skating  or  hopping  off and onto the membranes .
free diffusion rates for various lipids and lipid - attached peripheral proteins have been found to differ little from that of rhodopsin except in cases where structural proteins and fencing mechanisms can interfere , such as those found in red cell membranes ( spectrin , etc ) , that are designed to retain membrane proteins in functional , diffusion domains smaller than the order of 1m . in retinal rods ,
r * diffusion over 1um can yield 36x10g*/r * as we found experimentally . 13 .
membrane essentials : our lateral diffusion and signal transduction work provided an essential link at the dawn of recognition that biological membranes are 2-d liquid crystals where membrane proteins can be concentrated and permanently held in a molecular orientation functionally important to chemical reaction with other components while retaining rapid planar motion within the liquid .
membranes orient proteins and other components optimally for more efficient bimolecular reactions both within the membrane and from the aqueous phase . during the first years when i was doing these measurements , people were still speaking of membrane proteins as if they were stationary peanut butter , spread sheet - like over the tops of the lipid molecules .
thus , our work on large amphibian rods where disk membranes are wide enough to permit placement of more than one microbeam of measuring and interrogating light in msp , were the first to show in live continuous real - time that a receptor protein is in motion and to measure its speed as globular protein embedded in lipid . 14 .
gpcrs are enzymes : our discovery that r * is an enzyme capable of catalyzing gdp / gtp exchange with a turnover number of several thousand sec to powerfully amplify a weak biological signal was also the first recognition of a non - covalent mode of action by an enzyme . until this work
, enzymes were understood to mediate only covalent changes between substrate and product . in conclusion ,
i agree with vadim and marie that there is need for subsequent time and amplitude sculpting mediated by other proteins to explain the refinements of visual transduction in circumstances that need more time resolution and less amplification in brighter light or in those that require enhanced statistical properties of signal and noise for reliable single photon detection in dim light .
such modulation is consonant with the need for appropriately rapid action to capture or escape other organisms for survival in bright light in addition to seeing sensitively and reliably in near - darkness .
vadim mentions his later role in confirmation of my earlier discoveries of the extraordinary magnitude of r*-gase amplification .
none of this diminishes in any way the importance of the completely unexpected and extraordinarily rapid amplification of g protein activations resulting from single photon activation of a gpcr molecule , rhodopsin , that i discovered ~35 y ago and that still amazes me to this day .
i found that a single activated rhodopsin molecule is a non - covalent enzymatic amplifier , using the speed of short range lateral diffusion to encounter and activate thousands of copies of the gase , transducin , on a membrane surface .
the necessity for the properties of immense amplification , ultimate sensitivity and maximum speed in visual r*/gase / pde coupling and its absolute dependence on membrane lateral diffusion for expression of these essential properties that we discovered , underlies everything ! moreover , these same physical properties are intrinsic to all biological membranes .
they are the sine qua non of our gpcr membrane signal transducer mechanism . in this selective historical perspective on some of my early work that contributed to our most fundamental models of biological membranes including lateral diffusion on / in a membrane , signal amplification , and non - covalent enzyme actions , i have tried to highlight those aspects that address the question posed .
simply , can a single gef activate more than one gase and is there a pool of resultant freely diffusible , activated g protein that leaves the receptor to encounter its effector / gases ? in the case of the photoreceptor system i can answer definitively , yes . as sagaciously addressed in the accompanying article from eliot ross , it is still uncertain to what extent the rhodopsin / gt system is a perfect model for other receptor - g protein systems .
but i argue that the principles discovered through our work and that of others on the photoreceptor system are certainly relevant to all .
aspects of our discovery of lateral diffusion of the g protein coupled receptor ( gpcr ) rhodopsin and that a single activated rhodopsin can non - covalently catalyze gtp binding to thousands of gtpases per second on rod disk membranes via this diffusion are summarized herein . 
 rapid gtpase coupling to membrane - bound phosphodiesterase ( pde ) further amplifies the signal via cgmp hydrolysis , essential to visual transduction . 
 important generalizations from this work are that biomembranes can uniquely concentrate , orient for reaction and provide a solvent appropriate to rapid , powerful and appropriately controlled sequential interaction of signaling proteins . of equal importance 
 to function is timely control and termination of such powerful amplification via receptor phosphorylation ( quenching ) and arrestin binding . 
 downstream kinetic modulation by gtpase activating proteins ( gaps ) and regulators of g protein signaling ( rgs ) and related mechanisms as well as limitations set by membrane domain fencing , structural protein binding etc . can be essential in relevant systems .