Preheat oven to 400° F. Butter 9×13-inch casserole dish.
In 10-inch skillet, melt 1 tablespoon of butter over medium heat. Add shrimp and 1/2 teaspoon of Cajun seasoning and cook, stirring occasionally, until shrimp is pink and cooked through. Remove pan from heat; set aside.
Add pasta to boiling water and cook according to al dente according to package directions. Drain; set aside.
Meanwhile, melt 4 tablespoons butter in large saucepan over medium heat. Whisk in flour and cook about 1 minute, whisking constantly, until flour starts to brown a bit and smells nutty. Slowly add milk; whisking constantly. Allow sauce to come to simmer.
Once sauce reaches simmer; mix in 2 1/4 cups pepper jack and 1 1/2 cups cheddar cheese, adding a handful at a time, stirring with wooden spoon until completely melted before adding next handful. Season with remaining 1/2 teaspoon Cajun seasoning, salt and pepper; turn off heat.
Add cooked, drained pasta and shrimp to sauce. Stir with wooden spoon until ingredients are evenly distributed. Pour mixture into prepared casserole dish.
In small bowl, melt remaining 4 tablespoons butter. Add Panko crumbs; mix well. Sprinkle macaroni and cheese with remaining shredded cheeses. Sprinkle bread crumb mixture on top of cheese.
Bake until browned and bubbly, about 15 to 20 minutes. Let sit for 10 to 15 minutes before serving.