BISC 307L 2nd Edition Lecture 14 Current LectureTypes of Smooth MuscleThere are two main types of smooth muscles - single unit and multiunit. These terms refer to whether they act as a single unit or multiple units. In the single unit, the smooth muscle cells are coupled by extensive gap junctions. The excitation, whether by second messengers or depolarization, spreads through gap junctions so the whole thing behaves as one unit. You can see the autonomic postganglionic axon with synaptic boutons and varicosities releasing transmitters, and the types of smooth muscles that are of this sort occur throughout the body. But we will be focusing on the smooth muscle of blood vessels (constriction and dilation), in the intestine (responsible for motility), and in the full term uterus (powerful contractions during labor and delivery)Multi-unit: each cell works independently. Examples:1. the ones in the eye, such as the one that controls the iris, and the biliary body as shown above (when they contract, they change the shape of the lens and are responsible for accommodation – how your eyes focus when they are looking at something close).2. The non pregnant uterus, the smooth muscle is multiunit. At the end of pregnancy, in addition to proliferating, the smooth muscle cells become coupled through gap junctions. A few smooth muscles don’t receive any innervation. These tend to be intrinsically active, usually due to spontaneous changes in membrane potential. When we look at the heart, we cansee the ionic mechanism by which the cardiac muscle cells and especially the pacemaker have rhythmic intrinsic changes in membrane potential that result in periodic action potentials. Well, a similar thing happens to smooth muscles - the smooth muscles that don’t receive innervation are all single unit. They are subject to hormonal and paracrine control, but are not necessarily innervated.Most smooth muscles receive innervation from autonomic neurons though. In general, when they get depolarized, they contract, and when hyperpolarized, they relax. In addition, hormonesaffect all smooth muscles whether they are innervated or not. 2 paracrine agents that have been well studied influence the activity of smooth muscle – histamine (important regulator of inflammation – in the immune and circulatory system and allergic response) and nitric oxide, the gas which is synthesized by endothelial cells (innermost cells lining blood vessels). NO diffuses out to the muscles of the blood vessels and causes them to relax (important in regulation of blood flow in tissues). There are also stretch sensitive tissue in some muscles – example would be bladder – when it gets full, and smooth muscle gets stretched, they respond with depolarization and contract, increasing pressure on the bladder contents. Blood vessels do the same thing, because they have has stretch sensitive channels. Excitation due to the stretching of blood vessels is important in maintaining blood pressure. Regulation of Ca2+ in Smooth Muscle CellsAround the periphery of this figure are the mechanisms of Ca regulation. Start in upper left – we have a calcium channel that is coupled to a receptor for a hormone or neurotransmitter. When opened, Ca enters the cell down its electrochemical gradient. Ca has the greatest inward driving force of all ions.On the right, are vg channels that open due to depolarization, stretching, or depletion of intracellular calcium. We also have other ion channels in the upper right corner – for example, some vg-Na channels that can amplify depolarization. The number of Na channels in a smooth muscle is not usually enough to get an all or none AP out of the cell, and as a result, most smooth muscles do not have an AP. Instead, they have regenerative, but not all-or-none responses. There also exist K channels that exist in smooth muscle that dampen the excitability of the cell. There also tends to be a lot of Na/K pumps in the smooth muscle, which are highly electrogenic and contribute highly to the membrane potential. Ca channels in the plasma membrane are the most important source of Ca to trigger contractionin a multiunit smooth muscle. These are shown in the top half of this diagram. In the lower left corner is Ca being released by the binding of a ligand (NT or hormone) to a receptor that is coupled to phospholipase c, causing the release of IP3, which causes release of Ca from SR. This is the most important source of Ca in single unit smooth muscles.In the lower right quadrant of this diagram is where all of this Ca goes. It is pumped out of the membrane by Ca ATPases, or by Na/Ca antiports. Those are the mechanisms of Ca extrusion from the cell. We also havesequestration into theinternal reservoirs of the SR.There are Ca ATPases thatpump Ca into the SR. Newly Described PlasmaMembrane Ca Studies were done on a cellline derived from B-lymphocytes, but thesemechanisms generally occurin most cells, includingsmooth muscle. On the left, we see a ligandbinding to a receptor-coupled G protein, whichactivates phospholipase C, which produces IP3, which (going through bottom route), causes release of Ca from ER. Ca sequestered inside the ER is due to Ca pumping. The diagram reminds you that the IP3 receptor in the ER membrane is an IP3 gated cation channel (allows Ca and other cations to pass through it). That’s the well-known mechanism. What these papers show is that in this cell line and in other cells, there are a small number of Ip3 gated channels in the plasma membrane as well. When Ip3 binds, it opens this nonspecific cation channel and a specific amount of Ca comes in. There are a small number of these receptors in the membrane - 1 or 2 copies per cell. But they have a high conductance for Ca. (200 pS -siemen is the inverse of an OHM) is a lot. So this channel, when it is open, can cause a large calcium current. For an unknown reason, the rises in calcium by the 2 pathways have different time courses. Other studies identified a new Ca channel in the plasma membrane called Orai 1, which is a low conductance Ca channel. There are many copies - 1000’s per cell, so you have a lot of Ca influx. It is important because it is the molecular basis of store-operated calcium entry, or calcium-depletion gated calcium channels. When a cell gets depleted of Ca inside, the gate opens up andallows more Ca to come in. The Ca sensing protein in the ER membrane called STIM1 workstogether with the Orai 1. Stim 1 is an ER