BISC 307L 1st Edition Lecture 13 Current Lecture Types of Smooth Muscle o o How the cells behave o Left Single unit Blood vessels vasodilation and constriction intestine motility full term uterus contractions Coupled by gap junctions electrical and metabolic Excitation spreads through gap junctions whole thing behaves as a unit Varicosities releasing transmitter o Right Multi Unit Eye iris pupil ciliary body change shape of lens accommodation non pregnant uterus Cells are individual not coupled by gap junctions Each cell responds individually o Some smooth muscle doesn t receive any innervations Single unit Cyclically active intrinsically active Cardiac and pacemaker cells periodic action potentials Subject to hormone and paracrine control as is all smooth muscle Histamine inflammation Nitric Oxide synthesized by endothelial cells and causes relaxation of blood vessels o Most do receive innervations o Bladder is stretch sensitive o Vascular smooth muscle is also stretch sensitive maintenance of blood pressure Regulation of Ca2 i in smooth muscle cells o Trigger for contraction o Where does calcium come from Center is calcium Along periphery are mechanism for Calcium to come in Upper left Ca2 channel coupled to receptor for hormone or neurotransmitter Ca2 moves inwardly down electrochemical gradient Right 1 Ca2 channels that are voltage gated 2 Stretch activated mechanically gated ca2 channels 3 Open in response to depletion in Ca2 There are also voltage gated Na channels in right to amplify depolarization not usually an all or none action potential but is enough to open the Ca2 channels Most don t have action potential in smooth cells but you can have regenerative responses just not all or none Also have K channels to dampen the excitability of the cell Ca2 channels in the plasma membrane are the most important for triggering contraction in the MULTIUNIT cells There are always Na K pumps because they are highly electrogenic Lower left Binding of ligand to receptor that s coupled to PLC and generates IP3 that generates release of Ca2 from ER This is the most important for single unit systems Lower right Where the Ca2 goes 1 Removed by calcium ATPases 2 or by the Na Ca2 antiport one calcium out for every 3 sodium it lets in 3 Or sequestration of Ca2 back into the ER Newly Described plasma membrane Ca2 channels o o More realistic diagram of previous slide o Left side IP3 system coupled via G protein to PLC which produces the IP3 which causes release of Ca2 from ER This IP3 receptor in the ER membrane is an IP3 gated cation channel Ca2 Well known mechanism o This paper also shows that there are a small number of IP3 gated cation channels in the plasma membrane which can let in Ca2 from outside There are not very many of these receptors in membrane but they have capacitance for Ca2 to come through These channels can carry large calcium current and let a lot in o Time course different ER releases Ca2 rapidly but the plasma membrane channels are much slower but stay active for longer o New Ca2 channel in membrane pink Many copies but low conductance of calcium Important because this is the molecular basis for store operated calcium entry when cell is depleted of calcium First to show this mechanism o STIM1 is an ER membrane protein that normally when Ca2 levels in the ER are high the STIM1 proteins are scattered through membrane but if Ca2 levels are low in the ER then the STIM1 proteins aggregate in the membrane In this state the cytoplasmic side of this protein can bind to the OR1 calcium channel and that opens that channel o Shows that the regulation of Ca2 is complicated multiple pathways Crossbridge cycling in smooth muscle o Actin and myosin in smooth muscle o Crossbridges form between these two there s less of it so the force is much less than skeletal muscle o The time course is way slower and longer than skeletal muscle o This slide shows mechanism Thick filament and actin of thin filament and crossbridge of myosin molecule Dotted outline part Ca2 turns this on bound to calmodulin and when Ca2 binds it activates a kinase and the substrate of this kinase is myosin Light chain forms head of myosin molecule Phosphorylates head of the myosin which is important because crossbirdge cycling in smooth muscle requires phosphorylation of the myosin head Like a switch Faster cycling because it is faster than slow cycling but it is slow Faster cycling corresponds to the 6 step cycle from before When myosin head is phosphorylated it can cycle through those six steps this generates the force The phosphorylation of the myosin head to make this possible requires one ATP How do you turn it off Dephosphorylation of myosin head Specific myosin light chain phosphtase and the contraction is turned off There is regulation of the mechanism Part that isn t dotted The preferred substrate of the phosphatase is the unattached myosin head Has some activity to deattach the attached myosin head however but with much less activity On left attached but dephosphorylated myosin crossbridge Most of the product will be up in left corner Some small percentage of the cross bridges get in the state in the lower left corner called catch state because gets caught in this state The force gets built up allows SMOOTH MUSCLE TO MAINTAIN FORCE FOR LONG TIME Leaves this state by phosphorylating myosin head goes back to fast cycling Or can detach by binding ATP But ATP binding affinity of attached myosin head very low so usually the catch state is long Some invertebrates have similar mechanisms Clams clamp down very tightly for long times involves this catch state Introduction to Endocrine Physiology Things to Remember o 1 Names locations secretions of major endocrine organs Fig 7 2 o 2 General properties of peptide steroid and amine hormones Table 7 1 o 3 Synthesis storage and processing of peptides Fig 7 3 o 4 Synthesis and action of steroid hormones Figs 7 6 and 7 7 o 5 Tyrosine catecholamines and thyroid hormones Fig 7 8 o 6 Hormones of the posterior pituitary Fig 7 12 and anterior pituitary Negative Feedback in hypothalamic anterior pituitary systems o o Hypothalamus contains purple neurons that release hormones into the capillaries o Stimulating growth o Can see the negative feedback o The tropic hormone inhibits the releasing hormone